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WO1996005180A1 - Retroviral protease inhibiting 1,2,4-triazacycloheptanes - Google Patents

Retroviral protease inhibiting 1,2,4-triazacycloheptanes Download PDF

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Publication number
WO1996005180A1
WO1996005180A1 PCT/US1995/009472 US9509472W WO9605180A1 WO 1996005180 A1 WO1996005180 A1 WO 1996005180A1 US 9509472 W US9509472 W US 9509472W WO 9605180 A1 WO9605180 A1 WO 9605180A1
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Prior art keywords
benzyl
substituted benzyl
compound
loweralkyl
hydroxy
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PCT/US1995/009472
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French (fr)
Inventor
Chen Zhao
Dale J. Kempf
Hing L. Sham
Daniel W. Norbeck
David A. Betebenner
Shuqun Lin
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Abbott Laboratories
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Publication date
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Priority to AU31503/95A priority Critical patent/AU3150395A/en
Publication of WO1996005180A1 publication Critical patent/WO1996005180A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for treating a retroviral infection and in particular an HIV infection, processes for making such compounds and synthetic intermediates employed in these processes.
  • HIV human immunodeficiency virus
  • Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants.
  • RNA ribonucleic acid
  • DNA RNA-dependent deoxyribonucleic acid
  • retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and hepatic carcinomas in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
  • HIV-1 and HIV-2 human immunodeficiency viruses
  • HIV-2 acquired immune deficiency syndrome
  • hepatitis B virus which causes hepatitis and hepatic carcinomas in man
  • human T-cell lymphotrophic viruses I, II, IV and V which cause human acute cell leukemia
  • bovine and feline leukemia viruses which cause leukemia in domestic animals.
  • Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by the retrovirus.
  • protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I.
  • Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angioten
  • retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).
  • Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis.
  • Current treatments for AIDS involve administration of compounds such as 3'-azido-3'-deoxythymidine (AZT), 2',3'- dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddl) and 2',3'-didehydro-3'- deoxythymidine (d4T) and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
  • Preferred compounds of the invention are compounds of the formula B:
  • R 1 , R 2 , R 3 , R 4 and X are defined as above.
  • Preferred compounds of the invention are compounds of the formula A or B wherein R 1 is loweralkyl or arylalkyi; R 2 is R 2a -C(O)- wherein R 2a is
  • More preferred compounds of the invention are compounds of the formula A or B wherein R 1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R 2 is R 2a -C(O)- wherein R 2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R 3 and R 4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, benzyl, hydroxy- substituted benzyl, hydroxyalkyl-substituted benzyl, alkoxy-substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substitutents are hydroxy and alkoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2 is R 2a -C(O)- wherein R 2a is CH 3 -, CH 3 -(CH 2 ) 2 -.
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2 is R 2a -C(O)- wherein R 2a is CH 3 -, CH 3 -(CH 2 ) 2 -, (CH 3 ) 2 CHCH 2 -, CH 3 (CH 2 ) 3 -, (CH 3 (CH 2 ) 2 ) 2 CH-, cyclopentyl, HOCH 2 (CH 2 ) 3 -, HOCH 2 (CH 2 ) 2 - or HOCH 2 -;
  • R 3 and R 4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl
  • R 1 is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl
  • R 2 is R 2a -C(O)- wherein R 2a is CH 3 -, CH 3 -(CH 2 ) 2 -,
  • the especially preferred compounds of the invention are compounds of the formula A or B wherein R 1 is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl; R 2 is R 2a -C(O)- wherein R 2a is (CH 3 ) 2 CHCH 2 -; R 3 and R 4 are independently selected from 4-hydroxybenzyl, 4-aminobenzyl and
  • the compounds of the invention comprise asymmetrically substituted centers (i.e., asymmetrically substituted carbon atoms).
  • the present invention is intended to include all stereoisomeric forms of the compounds, including racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention.
  • the terms "S” and "R” configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981 )), which is hereby incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyi,
  • t-butylacetyl 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
  • 2,2,2,-trichloroethoxycarbonyl 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyi, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • O-protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981 )).
  • O-protecting groups comprise substituted methyl ethers, for example,
  • tetrahydropyranyl ethers substituted ethyl ethers, for example, 2,2,2- trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like.
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl,
  • alkylene refers to a straight or branched chain carbon diradical containing from 1 to 6 carbon atoms including, but not limited to, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 - and the like.
  • loweralkenyl refers to a loweralkyl radical which contains at least one carbon-carbon double bond including, but not limited to, propenyl, butenyl and the like.
  • aryl refers to a C 6 monocyclic aromatic ring system or a C 9 or C 10 bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, alkoxycarbonyl, alkanoyl, hydroxy, halo, mercapto, nitro, cyano, amino, alkylamino, dialkylamino, carboxaldehyde, carboxy, carboxamide, arylalkyi, arylalkoxy, (heterocyclic)alkyl, (heterocyclic)alkoxy, (heterocyclic)carbonylalkoxy, aminoalkyl, aminoalkoxy, alkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkyl, dialkylaminoalkoxy,
  • alkoxyalkyl)aminoalkyl (alkoxyalkyl)aminoalkyl, (alkoxyalkyl)aminoalkoxy, di-(alkoxyalkyl)aminoalkyl, di-(alkoxyalkyl)aminoalkoxy, (alkoxyalkyl)(alkyl)aminoalkyl,
  • substituted aryl groups include tetrafluorophenyl and
  • arylalkyi refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl, 4-hydroxybenzyl, 1 - naphthylmethyl and the like.
  • aminoalkyl refers to -NH 2 appended to a loweralkyl radical.
  • hydroxyalkyl refers to -OH appended to a loweralkyl radical.
  • dihydroxyalkyl refers to a loweralkyl radical disubstituted with -OH groups.
  • polyhydroxyalkyl refers to a loweralkyl radical substituted with more than two -OH groups.
  • mercaptoalkyl refers to a loweralkyl radical to which is appended a mercapto (-SH) group.
  • hydroxyaminoalkyl refers to a hydroxyamino group (-NHOH) appended to a loweralkyl radical.
  • alkoxyaminoalkyl refers to alkoxyaminoalkyl
  • (alkoxy) (alkyl)aminoalkyl refers to (R 2 1 )(R 22 )N- wherein R 21 is alkoxy and R 22 is loweralkyl appended to a loweralkyl radical.
  • alkylamino refers to a loweralkyl radical appended to an NH radical.
  • cycloalkyl refers to an aliphatic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
  • cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
  • cycloalkenyl refers to an aliphatic ring having 5 to 7 carbon atoms and a carbon-carbon double bond including, but not limited to, cyclopentenyl, cyclohexenyl and the like.
  • Cycloalkenyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
  • cycloalkenylalkyl refers to a cycloalkenyl group appended to a loweralkyl radical, including but not limited to
  • alkylaminocycloalkyl refers to an alkylamino group appended to a cycloalkyl radical.
  • dialkylaminocycloalkyl refers to a dialkylamino group appended to a cycloalkyl radical.
  • alkoxy and thioalkoxy refer to R 29 O- and R 29 S-, respectively, wherein R 29 is a loweralkyl group.
  • alkoxyalkyl refers to an alkoxy group
  • thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyl radical.
  • alkenyloxy refers to R 32 O- wherein R 32 is a loweralkenyl group.
  • hydroxyalkoxy refers to -OH appended to an alkoxy radical.
  • dihydroxyalkoxy refers to an alkoxy radical which is disubstituted with -OH groups.
  • arylalkoxy refers R 33 O- wherein R 33 is a arylalkyl group as defined above.
  • (heterocyclic)alkoxy refers to R 34 O- wheeein R 34 is a (heterocyclic)alkyl group.
  • aryloxyalkyl refers to a R 35 O- group appended to a loweralkyl radical, wherein R 35 is an aryl group.
  • dialkylamino refers to dialkylamino
  • R 36 and R 37 are independently selected from loweralkyl groups.
  • N-protected aminoalkyl refers to -NHR 40 appended to a loweralkyl group, wherein R 40 is an N-protecting group.
  • alkylaminoalkyl refers to -NHR 41 appended to a loweralkyl radical, wherein R 41 is a loweralkyl group.
  • N-protecting group and R 43 is loweralkyl.
  • dialkylaminoalkyl refers to -NR 44 R 45 which is appended to a loweralkyl radical wherein R 44 and R 45 are independently selected from loweralkyl.
  • carboxyalkyl refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
  • alkoxycarbonylalkyl refers to a R 46 C(O)- group appended to a loweralkyl radical, wherein R 46 is an alkoxy group .
  • carboxy alkoxyalkyl refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is appended to a loweralkyl radical.
  • alkoxycarbonylalkoxyalkyl refers to an alkoxycarbonyl group (R 47 C(O)- wherein R 47 is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.
  • (amino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH 2 ).
  • ((N-protected)amino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR 48 wherein R 48 is an N-protecting group.
  • (alkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an
  • ((N-protected)alkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR 48 R 49 wherein R 48 is as defined above and R 49 is a loweralkyl group.
  • (dialkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR 49 R 49 wherein R 49 is as defined above.
  • (amino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH 2 ).
  • ((N-protected)amino)alkoxy-carbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR 50 wherein R 50 is an N-protecting group.
  • (alkylamino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.
  • ((N-protected)alkylamino)alkoxy-carbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 51 R 52 wherein R 51 is an N-protecting group and R 52 is a loweralkyl group.
  • (dialkylamino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 53 R 54 wherein R 53 and R 54 are independently selected from loweralkyl.
  • aminocycloalkyl refers to an NH 2 appended to a cycloalkyl radical.
  • ((alkoxy)alkoxy)alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
  • polyalkoxyalkyl refers to a polyalkoxy residue appended to a loweralkyl radical.
  • polyalkoxy refers to -OR 67 wherein R 67 is a straight or branched chain containing 1 -5, C n ,-O-C n" linkages wherein n' and n" are independently selected from 1 to 3, including but not limited to
  • halo or halogen as used herein refers to -Cl, -Br, -I or -F.
  • haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.
  • thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyl radical.
  • alkylsulfonyl refers to R 93 SO 2 - wherein R 93 is loweralkyl group.
  • alkylsulfonylalkyl refers to an alkylsufonyl group appended to a loweralkyl radical.
  • arylthioalkyl refers to arylthioalkyl
  • aryloxyalkyl refers to aryloxyalkyl
  • R 94 -O-R 95 - wherein R 94 is an aryl group and R 95 is an alkylene group.
  • arylsulfonylalkyl refers to R 96 -S(O) 2 -R 97 - wherein R 96 is any aryl group and R 97 is an alkylene group.
  • (heterocyclic)oxyalkyl refers to R 98 -O-R 99 - wherein R 98 is a heterocyclic group and R 99 is an alkylene group.
  • (heterocyclic)thioalkyl refers to (heterocyclic)thioalkyl
  • (heterocyclic)sulfonylalkyl refers to (heterocyclic)sulfonylalkyl
  • arylalkoxyalkyl refers to R 104 -O-R 105 - wherein R 104 is an arylalkyi group and R 105 is an alkylene group, for example,
  • arylthioalkoxyalkyl refers to R 106 -S-R 107 - wherein R 106 is an arylalkyi group and R 107 is an alkylene group.
  • arylalkylsulfonylalkyl refers to R 108 -S(O) 2 -R 109- wherein R 108 is an arylalkyi group and R 109 is an alkylene group.
  • (heterocyclic)alkoxy refers to R 110 -O- wherein R 110 is a (heterocyclic)alkyl group, for example, 2-(morpholin-1 -yl)ethoxy and the like.
  • (heterocyclic)alkoxyalkyl refers to (heterocyclic)alkoxyalkyl
  • (heterocyclic)thioalkoxyalkyl refers to
  • (heterocyclic)alkylsulfonylalkyl refers to R 114 -S(O) 2 -R 115 - wherein R 114 is a (heterocyclic)alkyl group and R 115 is an alkylene group.
  • cycloalkyloxyalkyl refers to R 116 -O-R 117 - wherein R 116 is a cycloalkyl group and R 117 is an alkylene group.
  • cycloalkylthioalkyl refers to R 118 -S-R 119 - wherein R 118 is a cycloalkyl group and R 119 is an alkylene group.
  • cycloalkylsulfonylalkyl refers to cycloalkylsulfonylalkyl
  • cycloalkylalkoxyalkyl refers to cycloalkylalkoxyalkyl
  • cycloalkylthioalkoxyalkyl refers to cycloalkylthioalkoxyalkyl
  • cycloalkylalkylsulfonylalkyi refers to cycloalkylalkylsulfonylalkyi
  • R 126 -S(O)2-R 127 - wherein R 126 is a cycloalkylalkyl group and R 127 is an alkylene group.
  • alkanoyl refers to R k -C(O)- wherein R k is a loweralkyl group.
  • aminocarbonyl refers to aminocarbonyl
  • aminocarbonylalkyl refers to an aminocarbonyl group appended to a loweralkyl radical.
  • alkylaminocarbonyl refers to -C(O)NHR 128 wherein R 128 is loweralkyl.
  • alkylaminocarbonylalkyl refers to an alkylaminocarbonylalkyl
  • alkylaminocarbonyl group appended to a loweralkyl radical alkylaminocarbonyl group appended to a loweralkyl radical.
  • dialkylaminocarbonyl refers to dialkylaminocarbonyl
  • R 129 and R 130 are independently selected from loweralkyl.
  • dialkylaminocarbonylalkyl refers to a
  • dialkylaminocarbonyl group appended to a loweralkyl group
  • aroylalkyl refers to R 131 -C(O)-R 132 - wherein R 131 is an aryl group and R 132 is an alkylene group.
  • (heterocyclic)carbonylalkyl refers to
  • aminoalkoxy refers to an alkoxy radical to which is appended an amino (-NH 2 ) group.
  • alkylaminoalkoxy refers to an alkoxy radical to which is appended an alkylamino group.
  • dialkylaminoalkoxy refers to an alkoxy radical to which is appended a dialkylamino group.
  • (alkoxyalkyl)aminoalkyl refers to a loweralkyl radical to which is appended an (alkoxyalkyl)amino group.
  • (alkoxyalkyl)aminoalkoxy refers to an alkoxy radical to which is appended an (alkoxyalkyl)amino group.
  • (alkoxyalkyl)(alkyl)aminoalkyl refers to a loweralkyl radical to which is appended an (alkoxyalkyl)(alkyl)amino group.
  • (alkoxyalkyl)(alkyl)aminoalkoxy” as used herein refers to an alkoxy radical to which is appended an (alkoxyalkyl)(alkyl)amino group.
  • di-(alkoxyalkyl)aminoalkyl refers to a loweralkyl radical to which is appended an di-(alkoxyalkyl)amino group.
  • di-(alkoxyalkyl)aminoalkoxy refers to an alkoxy radical to which is appended an di-(alkoxyalkyl)amino group.
  • carboxyalkoxy refers to an alkoxy radical to which is appended a carboxy (-COOH) group.
  • aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (H 2 NC(O)-) group.
  • alkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
  • dialkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an dialkylaminocarbonyl group.
  • (heterocyclic)carbonylalkoxy refers to
  • arylalkoxycarbonylalkyl refers to R 137 -O-C(O)- R 138 - wherein R 137 is an arylalkyi group and R 138 is an alkylene group.
  • alkanoyl refers to R 139 -C(O)- wherein R 139 is a loweralkyl group.
  • aroyl refers to R 140 -C(O)- wherein R 140 is an aryl group.
  • alkylsulfonyl refers to R 141 -S(O) 2 - wherein R 141 is a loweralkyl group.
  • arylsulfonyl refers to R 142 -S(O) 2 - wherein R 142 is an aryl group.
  • heterocyclic ring or “heterocyclic” as used herein independently refers to a 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • the 5- membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring.
  • Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, tetrahydroqumolyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,
  • Heterocyclics also include:
  • Preferred heterocyclics are pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl and
  • Heterocyclics can also be substituted with a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphoHnyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which can be unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy.
  • nitrogen containing heterocycles can be N-protected.
  • heterocyclicalkyl refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to
  • naturally occurring ⁇ -amino acid refers to alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine,
  • glutamine aspartic acid, glutamic acid, lysine, arginine or histidine.
  • R 8 is hydrogen or an O-protecting group
  • R 9 and R 10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.
  • Preferred compounds of the formula C are those wherein R 1 is loweralkyl or arylalkyi and R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • a preferred N-protecting group R 9 is t-butyloxycarbonyl or
  • a preferred N-protecting group R 10 is t-butyloxycarbonyl or
  • More preferred compounds are compounds of the formula C wherein R 1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; and R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • Most highly preferred compounds are compounds of the formula C wherein R 1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R 2 is R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • Preferred compounds of the formula C also include compounds of the formula D:
  • R 8 is hydrogen or an O-protecting group
  • R 9 and R 10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.
  • Preferred compounds of the formula D are those wherein R 1 is loweralkyl or arylalkyl and R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • a preferred N-protecting group R 9 is t-butyloxycarbonyl or
  • a preferred N-protecting group R 10 is t-butyloxycarbonyl or
  • More preferred compounds are compounds of the formula D wherein R 1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl,
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • R 1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl;
  • R 8 is hydrogen or an O-protecting group
  • Preferred compounds of the formula E are those wherein R 1 is loweralkyl or arylalkyi; R 2b is benzyl and R 8 is an O-protecting group.
  • Preferred compounds of formula E also include compounds of the formula F:
  • R 8 is hydrogen or an O-protecting group
  • Preferred compounds of the formula F are those wherein R 1 is loweralkyl or arylalkyi; R 2b is benzyl and R 8 is an O-protecting group.
  • the compounds of the invention can be prepared as shown in Schemes 1 - 5.
  • the schemes outline the preparation of the compounds of the invention having the preferred stereochemistry.
  • other stereoisomers of the compounds of the invention can be prepared by starting with the aminoalcohol having the opposite stereochemistry to that shown for compound 1 in Scheme 1.
  • oxidation for example, Swern oxidation
  • Olefination for example, by Wittig reaction
  • N-protected aldehyde 2 provides olefin 3.
  • Epoxidation of olefin 3 (for example, with m-chloroperbenzoic acid (MCPBA)) provides a mixture of epoxides 4 and 5. Separation of the epoxides (for example, by chromatography) provides the desired epoxide isomer 4.
  • reaction of N-protected hydrazine 6 (R 10 is an N-protecting group, for example, benzyloxycarbonyl) with an aldehyde or ketone derivative of substituent R2b provides hydrazone 7.
  • Reduction of hydrazone 7 (for example, by hydrogenation) provides hydrazine 8.
  • reaction of epoxide 4 with hydrazine 8 provides hydroxy hydrazine 9.
  • Protection of the hydroxyl group with an O-protecting group for example, trimethylsilylethoxymethyl, methoxyethoxymethyl or methoxymethyl and the like) provides 10.
  • Removal of N-protecting groups provides 11.
  • reaction of 11 with Q-X-Q' provides 12.
  • Q and Q" are, for example, independently selected from imidazolyl, N-succinimidyloxy, -O-phenyl, halogen and the like.
  • Q and Q' are, for example, imidazolyl and the like.
  • a sulfonate mesylate, tosylate, triflate and the like
  • a halogen and the like a halogen and the like
  • R 2 can be introduced by first removing the N-protecting group R 2b from compound 12 (by hydrogenation or other suitable N-debenzylation method) to give 13. Acylation or sulfonylation of 13 with R 2 -Z wherein R 2 -Z is a carboxylic acid halide or sulfonyl halide and the like provides 14.
  • a sulfonate mesylate, tosylate, triflate and the like
  • a halogen and the like a halogen and the like
  • triphenylmethylphosphonium bromide To this was added 70 ml of THF, cooled to 0°C and 4.42 g of 35% potassium hydride dispersion in oil was added. The mixture was stirred at RT for 24 h. To this mixture was added 30 ml of toluene and let stand for 30 min. The supernatant was cannulated over into a solution of 3.37 g of N-((benzyloxy)carbonyl)-D-phenylalaninal in 50 ml of toluene at -78°C. The reaction mixture was stirred at -78°C for 2 h, followed by 0.5 h at RT. Satd. ammonium chloride (50 ml) was added.
  • Example 1 D To a solution of 1.2 g of the product of Example 1 C in 36 ml of isopropanol was added 1.03 g of the hydrazine from Example 1 D. The solution was heated at reflux for 24 h; cooled to RT and concentrated in vacuo. Silica gel column chromatography (10% to 20% acetone/hexane) provided 1.5 g of desired product.
  • Example 1 G (in 5 ml of CH 2 CI 2 ) over a period of 2 h via a syringe pump. The solution was kept at RT for 72 h; concentration in vacuo and purification by silica gel column chromatography (20% EtOAc/CH 2 Cl 2 ) provided 400 mg of desired compound.
  • Example 1H To a suspension of 72 mg of 20% palladium hydroxide on carbon in 36 ml of methanol was added 360 mg of the product of Example 1H. The mixture was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 285.0 mg of the desired product.
  • Example 1L Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 2B, provided the desired compound.
  • Example 1J Using the procedure of Example 1J, but replacing the benzoyl chloride with isobutyryl chloride, provided the desired compound.
  • 1 H NMR (CDCI 3 ) ⁇ 0.03 (s, 9H), 0.96 (t, 2H), 1.12 (d, 6H), 2.79 (m, 1H), 2.94 (m, 1H), 3.11 (m, 1H), 3.21 (m, 1H), 3.70 (m, 3H), 4.08 (m, 1H), 4.41 (br s, 1H), 4.71 (d, 1H), 4.77 (m, 1H), 4.85 (d, 1H), 6.74 (br s, 1H), 7.18 (m, 2H), 7.25-7.35 (m, 3H).
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 4A, provided the desired compound.
  • Example 1L Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 4B , provided the desired compound.
  • 1H NMR (CDCI 3 ) ⁇ .65 (t, 3H), 0.99 (d, 3H), 1.03 (t, 3H), 1.14 (d, 3H),1.22 (m, 2H), 1.78 (m, 2H), 1.91 (m, 1H), 2.74 (m, 1H), 2.88 (dd, 1H), 3.03 (m, 3H), 3.15 (m, 1H), 3.41 (m, 1H), 3.92 (m, 1H), 4.06 (ddd, 1H), 4.58 (dd, 1H), 7.19-7.33 (m, 5H). Mass spectrum:
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 5A, provided the desired compound.
  • Example 1L Using the procedure of Example 1L, but replacing the product from Example 1K with the product of Example 7B and replacing the allyl bromide with bromomethyl cyclopropane, provided the desired compound.
  • Example 1J Using the procedure of Example 1J , but replacing the benzoyl chloride with 2-furoyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 2A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ 1.83, 1.87 and 2.03 (three s, 3H), 2.33-2.45 (m, 1H), 2.60 (m, 1H), 2.73 (m, 1H), 2.83 (m, 1H), 3.13-3.23 (m, 1H), 3.55-3.68 (m, 1H), 3.95, 4.17 and 4.25 (three d, 1H), 4.28, 4.36 and 4.55 (three d, 1H), 4.89, 4.92 and 4.96 (three d, 1H), 5.36, 5.38 and 5.48 ( three d, 1H), 6.63 (m, 4H), 6.78 (m, 2H), 7.02 (m, 2H), 7.17-7.34
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 4A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 11 A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-d 6 ) (mixture of three rotamers) 0.81 and 0.94 (three t, 3H), 1.44-1.57, (m, 2H), 2.34-2.67 (m, 1H), 2.73-2.97 (m, 2H), 3.22 (m, 1H), 3.63-3.72 (m, 1H), 3.98 (m, 1H), 4.12-4.23 (m, 1H), 4.22-4.56 (three d, 1H), 4.85-4.98 (three d, 1H), 5.33-5.47 (three d, 1H), 6.60-6.79 (m, 6H), 6.98-7.35 (m, 7H), 9.33 (br s, 1H), 9.46 (br s, 1H).
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 13A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ .81, 0.87 and 0.92 (three t, 3H), 1.19, 1.37 and 1.52 ( three m, 4H), 1.90, 2.13 and 1.32 (three m, 2H), 2.39 (m, 1H), 2.62- 2.97 (m, 3H), 3.07-3.22 (m, 1H), 3.60-3.65 (m, 1H), 3.92, 3.96 and 4.03 (three d, 1H), 3.97, 4.16 and 4.21 (three d, 1H), 4.29, 4.38 and 4.52 (three d, 1H), 4.83, 4.89 and 4.95 (three d, 1H), 5.35, 5.38 and 5.47 (three d,
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 14A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 0.75-0.96 (three m, 6H), 1.25-1.58 (three m, 4H), 2.36-2.46 (m, 1H), 2.65-2.85 (m, 3H), 3.15-3.25 (m, 2H), 3.68 (m, 1H), 3.95 (d, 1H), 4.10 (m, 1H), 4.38 (d, 1H), 4.95, 5.06 and 5.13 (three d, 1H), 5.38, 5.40 and 5.44 (three d, 1H), 6.57-6.63 (m, 4H), 6.87 (dd, 2H), 6.90 (dd, 1H), 7.12 (dd, 1H), 7.22-7.32
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 15A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 0.72, 0.85 and 0.87 (three t, 6H), 1.18-1.57 (m, 8H), 2.28-2.38 (m, 1H), 2.58-3.18 (m, 5H), 3.67 (dd, 1H), 3.97 (d, 1H), 4.03, 4.07 and 4.11 (three d, 1H), 4.12, 4.37 and 4.58 (three d, 1H), 4.94, 5.08 and 5.15 (three d, 1H), 5.35, 5.40 and 5.42 (three d, 1H), 6.52-6.63 (m, 4H), 6.74-6.79 (m, 2H), 6.87 (m, 1H), 7.09-7.16(
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 16A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 1.94-1.85 (m, 8H), 2.23-2.30 (m, 1H), 2.61-3.18 (m, 5H), 3.66 (d, 1H), 3.98, 4.01 and 4.03 (three d, 1H), 4.08, 4.17 and 4.22 (three d, 1H), 4.30, 4.42 and 4.57 (three d, 1H), 4.82, 4.84 and 5.01 (three d, 1H), 5.31, 5.35 and 5.46 (three d, 1H), 6.58-6.66 (m, 4H), 6.73-6.79 (m, 2H), 6.97-6.99 (m, 1H), 7.09-7.15 (m, 2H), 7.19
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 7B and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 18A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 21 C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 1.34-1.61 (m, 4H), 2.07-2.47 (m, 2H), 2.55-2.96 (m, 3H), 3.16-3.24 (m, 3H), 3.38-3.46 (m, 1H), 3.60-3.65 (m, 1H), 3.94- 4.02 (m, 1H), 4.09, 4.10 and 4.12 (three d, 1H), 4.15, 4.23 and 4.25 (three d, 1H), 4.37, 4.40 and 4.46 (three t, 1H), 4.54, 4.90 and 4.97 (three d, 1H), 5.34, 5.37 and 5.46 (three d, 1H), 6.60-6.62 (m, 4H
  • Example 21 A with the product of Example 22A, provided the desired compound. Mass spectrum: (M+NH) + 438.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 22C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ 1.57-1.75 (m, 2H), 2.32-2.47 (m, 2H), 2.56-2.90 (m, 3H), 3.15-3.22 (m, 3H), 3.42-3.47 (m, 1H), 3.63 (m, 1H), 3.97 (m, 1H), 4.08, 4.10 and 4.13 (three d, 1H), 4.15, 4.24 and 4.38 (three d, 1H), 4.48, 4.54 and 4.56 (three t, 2H), 4.894.93 and 5.02 (three d, 1H), 5.36, 5.38 and 5.44 (three d, 1H), 6.61 (m, 4H), 6.76-6.79 (m,
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 23C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ 2.58-2.79 (m, 3H), 3.10-3.25 (m, 2H), 3.39-3.48 (m, 1H), 3.65 (m, 1H), 3.87 (m, 1H), 4.08 (d, 1H), 4.33, 4.39 and 4.46 (three d, 2H), 4.80, 4.94 and 4.95 (three d, 1H), 5.43, 5.46 and 5.61 (three d, 1H), 6.64-6.76 (m, 6H), 7.03-7.33 (m, 7H), 7.73, 7.98 and 8.12 (three s, 1H), 9.30,9.33, 9.35, 9.43, 9.47 and 9.50 (six s,
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 3-nitrobenzyl bromide, provided the desired compound.
  • 1 H NMR (DMSO-d 6 ) (mixture of three rotamers) 0.65-0.94 (six d, 6H), 1.54-2.37 (m, 4H), 2.64-3.22 (m, 3H), 3.32-4.18 (m, 3H), 4.26-4.32 (m, 1H), 4.48-4.60 (m, 1H), 5.14, 5.17 and 5.18 (three d, 1H), 5.46, 5.50 and 5.51 (three d, 1H), 6.86-8.41 (m, 13H).
  • Mass spectrum: (M+ H)+ 576.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 4-nitrobenzyl bromide, provided the desired compound.
  • 1 H NMR (DMSO-d 6 ) (mixture of two rotamers) 0.68-0.94 (four d, 6H), 1.57-2.38, (m, 4H), 2.63-3.20 (m, 3H), 3.31-4.16 (m, 3H), 4.25 and 4.31 (two d, 1H), 4.49 and 4.57 (two dd, 1H), 5.15 and 5.16 (two d, 1H), 5.44 and 5.49 (two d, 1H), 6.86-8.32 (m, 13H).
  • Mass spectrum: (M+ H)+ 576.
  • Tables 1 -128 can be prepared.
  • Ph represents phenyl.
  • the inhibitory potency of the compounds of the invention can be determined by the following method.
  • a compound of the invention is dissolved in DMSO and a small aliquot further diluted with DMSO to 100 times the final concentration desired for testing.
  • the reaction is carried out in a 6 X 50 mm tube in a total volume of 300 microliters.
  • the final concentrations of the components in the reaction buffer are: 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 ⁇ M fluorogenic substrate, 2% (v/v)
  • reaction mixture is placed in the fluorometer cell holder and incubated at 30°C for several minutes.
  • the reaction is initiated by the addition of a small aliquot of cold HIV protease.
  • the fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time.
  • the reaction rate is determined for the first six to eight minutes. The observed rate is directly proportional to the moles of substrate cleaved per unit time. The percent inhibition is 100 X (1 - (rate in presence of inhibitor)/(rate in absence of inhibitor)).
  • Table I shows the inhibitory potencies of compounds of the invention against HIV-1 protease.
  • the anti-HIV activity of the compounds of the invention can be determined in MT4 cells according to the procedure of Kempf, et. al.
  • the IC 50 is the
  • the LC 50 is the concentration of compound at which 50% of the cells remain viable.
  • Table II shows the inhibitory potencies of compounds of the invention against HIV-1 38 in MT4 cells.
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate
  • the basic nitrogen- containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
  • esters examples include a hydroxyl-substituted compound of formula A or B which has been acylated with a naturally occurring ⁇ -amino acid residue which is optionally N-protected, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R*C(O)- or R*C(S)- wherein R* is hydrogen, loweralkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula R a -C(R b )(R d )-C(O)- or R a - C(R b )(R d )-C(S)- wherein R b and R d are independently selected from hydrogen and loweralkyl and R a is -N(R e )(
  • R 180 NH(CH 2 ) 2 OCH 2 C(O)- wherein R 1 80 is hydrogen, loweralkyl, arylalkyl. cycloalkylalkyl, alkanoyl, benzoyl or a naturally occurring ⁇ -amino acyl group.
  • the amino acid esters of particular interest are those derived from the naturally occurring ⁇ -amino acids, however, other amino acid residues can also be used, including those wherein the amino acyl group is -C(O)CH 2 NR 200 R 201 wherein R 200 and R 201 are independently selected from hydrogen and loweralkyl or the group -NR 200 R 201 forms a nitrogen containing heterocyclic ring.
  • esters serve as pro-drugs of the compounds of the present invention and also serve to increase the solubility of these substances in the gastrointestinal tract. These esters also serve to increase solubility for intravenous administration of the compounds.
  • Other prodrugs include a hydroxyl-substituted compound of formula A or B wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R g )OC(O)R 181 or -CH(R g )OC(S)R 181 wherein R 181 is loweralkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R g is hydrogen, loweralkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.
  • Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding
  • the prodrugs of this invention are metabolized in vivo to provide the hydroxyl-substituted compound of formula A or B.
  • the preparation of the prodrug esters is carried out by reacting a hydroxyl-substituted compound of formula A or B with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to provide the desired pro-drug ester.
  • Prodrugs of the invention can also be prepared by alkylation of the hydroxyl group with (haloalkyl)esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
  • the compounds of the invention are useful for inhibiting retroviral protease, in particular HIV protease, in vitro or in vivo (especially in mammals and in particular in humans).
  • the compounds of the present invention are also useful for the inhibition of retroviruses in vivo, especially human
  • immunodeficiency virus HIV
  • the compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, in a human or other mammal.
  • Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from about 0.001 to about 1000 mg/kg body weight daily and more usually from about 0.1 to about 50 mg/kg body weight daily.
  • Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes
  • subcutaneous injections intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents, other antiinfective agents or vaccines.
  • Other antiviral agents to be administered in combination with a compound of the present invention include AL-721 , beta interferon,
  • reverse transcriptase inhibitors for example, zalcitabine (ddC), didanosine (ddl), BCH-189, AzdU, carbovir, DDA, D4C, stavudine (d4T), DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia-dideoxycytidine, PMEA, zidovudine (AZT) and the like
  • non-nucleoside reverse transcriptase inhibitors for example, R82193, L-697,661 , BI-RG-587 (nevirapine
  • retroviral protease inhibitors for example, HIV protease inhibitors such as Ro 31 -8959, SC-52151 , KNI-227, KNI-272 and the like
  • HEPT compounds L,697,639, R82150, U- 87201 E and the like
  • TAT inhibitors for example, RO-24-7429 and the like
  • nucleophosphoprotein ansamycin LM 427, trimetrexate, UA001 , ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cylobut-G, cyclobut-A, ara-M, BW882C87, foscamet, BW256U87, BW348U87, L-693,989, BV ara-U, CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109, TI-23, trifluridine, vidarabine, famciclovir, penciclovir, acyclovir, ganciclovir, castanospermine, rCD4/CD4-lgG, CD4-PE40, butyl-DNJ, hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate.
  • Immunomodulators that can be administered in combination with a compound of the present invention include bropirimine, Ampligen, anti-human alpha interferon antibody, colony stimulting factor, CL246,738, lmreg-1 , lmreg-2, diethydithiocarbamate, interleukin-2, alpha- interferon, inosine pranobex, methionine enkephalin, muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis facator, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha interferon immunoglobulin, IGF-1 , anti-Leu-3A, autovaccination, biostimulation, extracorporeal photophoresis, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine, IVIG,
  • pentamidine isethionate Any of a variety of HIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with a variety of HIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn
  • agents that can be used in combination with the compounds of this invention are ansamycin LM 427, apurinic acid, ABPP, AI-721 , carrisyn, AS-101 , avarol, azimexon, colchicine, compound Q, CS-85, N-acetyl cysteine, (2- oxothiazolidine-4-carboxylate), D-penicillamine, diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1 , monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T, pine cone extract, polymannoacetate, reticulose
  • agents that can be used in combination with the compounds of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin and the like.
  • antibactehals such as amikacin sulfate, azithromycin,
  • anti-neoplasties such as alpha interferon, COMP
  • cyclophosphamide, vincristine, methotrexate and prednisone cyclophosphamide, vincristine, methotrexate and prednisone
  • etoposide mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone)
  • PRO-MACE/MOPP prednisone, methotrexate (w/leucovin rescue)
  • vincristine vinblastine
  • angioinhibins pentosan polysulfate, platelet factor 4 and SP-PG and the like.
  • agents that can be used in combination with the compounds of this invention are drugs for treating neurological disease such as peptide T, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparin and cytosine arabinoside and the like.
  • agents that can be used in combination with the compounds of this invention are anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflomithine, 566C80, fansidar, furazolidone, L, 671 , 329, letrazuril, metronidazole, paromycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.
  • anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflomithine, 566C80, fansidar, furazolidone, L, 671 , 329, letrazuril, met
  • Among the preferred agents for treatment of HIV or AIDS in combination with the compounds of this invention are reverse transcriptase inhibitors.
  • agents which can be combined with the compounds of the present invention for the treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but include in principle any agents useful for the treatment or prophylaxis of AIDS or an HIV infection.
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

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Abstract

A retriviral protease inhibiting compound of formula (A) is disclosed.

Description

RETROVIRAL PROTEASE INHIBITING COMPOUNDS
This is a continuation-in-part of U.S. patent application Serial No.
286,380, filed August 9, 1994.
Technical Field
The present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for treating a retroviral infection and in particular an HIV infection, processes for making such compounds and synthetic intermediates employed in these processes.
Background of the Invention
Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants. Some of the more important retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and hepatic carcinomas in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by the retrovirus.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. 53.899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS involve administration of compounds such as 3'-azido-3'-deoxythymidine (AZT), 2',3'- dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddl) and 2',3'-didehydro-3'- deoxythymidine (d4T) and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Disclosure of the Invention
In accordance with the present invention, there are compounds of the formula A:
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
X is
(i) -C(=Y)- wherein Y is O, S or N(R5) wherein R5 is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro;
(ii) -S(O)- or
(iii) -S(O)2-;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Preferred compounds of the invention are compounds of the formula B:
Figure imgf000010_0001
wherein R1 , R2, R3, R4 and X are defined as above.
Preferred compounds of the invention are compounds of the formula A or B wherein R1 is loweralkyl or arylalkyi; R2 is R2a-C(O)- wherein R2a is
loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R3 and R4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, arylalkyl or (heterocyclic)alkyl; and X is -C(=O)-, -C(=N-OH)-, -C(=N-CN)- or -S(O)2-.
More preferred compounds of the invention are compounds of the formula A or B wherein R1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R2 is R2a-C(O)- wherein R2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R3 and R4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, benzyl, hydroxy- substituted benzyl, hydroxyalkyl-substituted benzyl, alkoxy-substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substitutents are hydroxy and alkoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-, -C(=N-OH)-, -C(=N-CN)- or -S(O)2-.
Even more preferred compounds of the invention are compounds of the formula A or B wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3-(CH2)2-. (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2 ) CH-, cyclopentyl, HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)- or -S(O)2-.
Even more highly preferred compounds of the invention are compounds of the formula A or B wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3-(CH2)2-, (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl, HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-.
Most highly preferred compounds of the invention are compounds of the formula A or B wherein R1 is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3-(CH2)2-,
(CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl, HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-.
The especially preferred compounds of the invention are compounds of the formula A or B wherein R1 is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl; R2 is R2a-C(O)- wherein R2a is (CH3)2CHCH2-; R3 and R4 are independently selected from 4-hydroxybenzyl, 4-aminobenzyl and
3-aminobenzyl; and X is -C(=O)-.
The compounds of the invention comprise asymmetrically substituted centers (i.e., asymmetrically substituted carbon atoms). The present invention is intended to include all stereoisomeric forms of the compounds, including racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981 )), which is hereby incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyi,
t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1 -methylethoxycarbonyl,
α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,
2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyi, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981 )).
O-protecting groups comprise substituted methyl ethers, for example,
methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, t-butyl, benzyl and triphenylmethyl;
tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2- trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl,
1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "alkylene" as used herein refers to a straight or branched chain carbon diradical containing from 1 to 6 carbon atoms including, but not limited to, -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2- and the like.
The term "loweralkenyl" as used herein refers to a loweralkyl radical which contains at least one carbon-carbon double bond including, but not limited to, propenyl, butenyl and the like.
The term "aryl" as used herein refers to a C6 monocyclic aromatic ring system or a C9 or C10 bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, alkoxycarbonyl, alkanoyl, hydroxy, halo, mercapto, nitro, cyano, amino, alkylamino, dialkylamino, carboxaldehyde, carboxy, carboxamide, arylalkyi, arylalkoxy, (heterocyclic)alkyl, (heterocyclic)alkoxy, (heterocyclic)carbonylalkoxy, aminoalkyl, aminoalkoxy, alkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkyl, dialkylaminoalkoxy,
(alkoxyalkyl)aminoalkyl, (alkoxyalkyl)aminoalkoxy, di-(alkoxyalkyl)aminoalkyl, di-(alkoxyalkyl)aminoalkoxy, (alkoxyalkyl)(alkyl)aminoalkyl,
(alkoxyalkyl)(alkyl)aminoalkoxy, hydroxyalkyl, hydroxyalkoxy, carboxyalkyl, carboxyalkoxy, alkoxyalkyl, thioalkoxyalkyl, polyalkoxyalkyl and dialkoxyalkyl. In addition, substituted aryl groups include tetrafluorophenyl and
pentafluorophenyl.
The term "arylalkyi" as used herein refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl, 4-hydroxybenzyl, 1 - naphthylmethyl and the like.
The term "aminoalkyl" as used herein refers to -NH2 appended to a loweralkyl radical.
The term "hydroxyalkyl" as used herein refers to -OH appended to a loweralkyl radical.
The term "dihydroxyalkyl" as used herein refers to a loweralkyl radical disubstituted with -OH groups.
The term "polyhydroxyalkyl" as used herein refers to a loweralkyl radical substituted with more than two -OH groups.
The term "mercaptoalkyl" as used herein refers to a loweralkyl radical to which is appended a mercapto (-SH) group.
The term "hydroxyaminoalkyl" as used herein refers to a hydroxyamino group (-NHOH) appended to a loweralkyl radical.
The term "alkoxyaminoalkyl" as used herein refers to
-NHR20 (wherein R20 is an alkoxy group) appended to a loweralkyl radical.
The term "(alkoxy) (alkyl)aminoalkyl" as used herein refers to (R2 1)(R22)N- wherein R21 is alkoxy and R22 is loweralkyl appended to a loweralkyl radical.
The term "alkylamino" as used herein refers to a loweralkyl radical appended to an NH radical.
The term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl. The term "cycloalkenyl" as used herein refers to an aliphatic ring having 5 to 7 carbon atoms and a carbon-carbon double bond including, but not limited to, cyclopentenyl, cyclohexenyl and the like. Cycloalkenyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
The term "cycloalkenylalkyl" as used herein refers to a cycloalkenyl group appended to a loweralkyl radical, including but not limited to
cyclohexenylmethyl.
The term "alkylaminocycloalkyl" as used herein refers to an alkylamino group appended to a cycloalkyl radical.
The term "dialkylaminocycloalkyl" as used herein refers to a dialkylamino group appended to a cycloalkyl radical.
The terms "alkoxy" and "thioalkoxy" as used herein refer to R29O- and R29S-, respectively, wherein R29 is a loweralkyl group.
The term "alkoxyalkyl" as used herein refers to an alkoxy group
appended to a loweralkyl radical.
The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group appended to a loweralkyl radical.
The term "guanidinoalkyl" as used herein refers to a guanidino group (-NHC(=NH)NH2) appended to a loweralkyl radical.
The term "alkenyloxy" as used herein refers to R32O- wherein R32 is a loweralkenyl group.
The term "hydroxyalkoxy" as used herein refers to -OH appended to an alkoxy radical.
The term "dihydroxyalkoxy" as used herein refers to an alkoxy radical which is disubstituted with -OH groups.
The term "arylalkoxy" as used herein refers R33O- wherein R33 is a arylalkyl group as defined above.
The term "(heterocyclic)alkoxy" as used herein refers to R34O- wheeein R34 is a (heterocyclic)alkyl group. The term "aryloxyalkyl" as used herein refers to a R35O- group appended to a loweralkyl radical, wherein R35 is an aryl group.
The term "dialkylamino" as used herein refers to
-NR36R37 wherein R36 and R37 are independently selected from loweralkyl groups.
The term "N-protected aminoalkyl" as used herein refers to -NHR40 appended to a loweralkyl group, wherein R40 is an N-protecting group.
The term "alkylaminoalkyl" as used herein refers to -NHR41 appended to a loweralkyl radical, wherein R41 is a loweralkyl group.
The term "(N-protected)(alkyl)aminoalkyl" as used herein refers to
-NR42R43, which is appended to a loweralkyl radical, wherein R42 is an
N-protecting group and R43 is loweralkyl.
The term "dialkylaminoalkyl" as used herein refers to -NR44R45 which is appended to a loweralkyl radical wherein R44 and R45 are independently selected from loweralkyl.
The term "carboxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
The term "alkoxycarbonylalkyl" as used herein refers to a R46C(O)- group appended to a loweralkyl radical, wherein R46 is an alkoxy group .
The term "carboxy alkoxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is appended to a loweralkyl radical.
The term "alkoxycarbonylalkoxyalkyl" as used herein refers to an alkoxycarbonyl group (R47C(O)- wherein R47 is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.
The term "(amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH2).
The term "((N-protected)amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR48 wherein R48 is an N-protecting group. The term "(alkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an
alkylamino group.
The term "((N-protected)alkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR48R49 wherein R48 is as defined above and R49 is a loweralkyl group.
The term "(dialkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR49R49 wherein R49 is as defined above.
The term "(amino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH2).
The term "((N-protected)amino)alkoxy-carbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR50 wherein R50 is an N-protecting group.
The term "(alkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.
The term "((N-protected)alkylamino)alkoxy-carbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR51 R52 wherein R51 is an N-protecting group and R52 is a loweralkyl group.
The term "(dialkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR53R54 wherein R53 and R54 are independently selected from loweralkyl.
The term "aminocycloalkyl" as used herein refers to an NH2 appended to a cycloalkyl radical.
The term "((alkoxy)alkoxy)alkyl" as used herein refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
The term "polyalkoxyalkyl" as used herein refers to a polyalkoxy residue appended to a loweralkyl radical. The term "polyalkoxy" as used herein refers to -OR67 wherein R67 is a straight or branched chain containing 1 -5, Cn,-O-Cn" linkages wherein n' and n" are independently selected from 1 to 3, including but not limited to
methoxyethoxymethoxy, methoxymethoxy and the like.
The term "halo" or "halogen" as used herein refers to -Cl, -Br, -I or -F.
The term "haloalkyl" as used herein refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.
The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group appended to a loweralkyl radical.
The term "alkylsulfonyl" as used herein refers to R93SO2- wherein R93 is loweralkyl group.
The term "alkylsulfonylalkyl" as used herein refers to an alkylsufonyl group appended to a loweralkyl radical.
The term "arylthioalkyl" as used herein refers to
R94-S-R95- wherein R95 is an aryl group and R95 is an alkylene group.
The term "aryloxyalkyl" as used herein refers to
R94-O-R95- wherein R94 is an aryl group and R95 is an alkylene group.
The term "arylsulfonylalkyl" as used herein refers to R96-S(O)2-R97- wherein R96 is any aryl group and R97 is an alkylene group.
The term "(heterocyclic)oxyalkyl" as used herein refers to R98-O-R99- wherein R98 is a heterocyclic group and R99 is an alkylene group.
The term "(heterocyclic)thioalkyl" as used herein refers to
R100-S-R101- wherein R100 is a heterocyclic group and R101 is an alkylene group.
The term "(heterocyclic)sulfonylalkyl" as used herein refers to
R 102-S(O)2-R103- wherein R102 is a heterocyclic group and R103 is an alkylene group.
The "arylalkoxyalkyl" as used herein refers to R104-O-R 105- wherein R 104 is an arylalkyi group and R105 is an alkylene group, for example,
benzyloxymethyl and the like. The "arylthioalkoxyalkyl" as used herein refers to R106-S-R107- wherein R106 is an arylalkyi group and R107 is an alkylene group.
The "arylalkylsulfonylalkyl" as used herein refers to R108-S(O)2-R109- wherein R108 is an arylalkyi group and R 109 is an alkylene group.
The term "(heterocyclic)alkoxy" as used herein refers to R110-O- wherein R110 is a (heterocyclic)alkyl group, for example, 2-(morpholin-1 -yl)ethoxy and the like.
The term "(heterocyclic)alkoxyalkyl" as used herein refers to
R1 10-O-R11 1- wherein R110 is a (heterocyclic)alkyl group and R11 1 is an alkylene group.
The term "(heterocyclic)thioalkoxyalkyl" as used herein refers to
R 112-S-R 113- wherein R112 is a (heterocyclic)alkyl group and R 1 13 is an alkylene group.
The term "(heterocyclic)alkylsulfonylalkyl" as used herein refers to R114-S(O)2-R 115- wherein R 114 is a (heterocyclic)alkyl group and R115 is an alkylene group.
The term "cycloalkyloxyalkyl" as used herein refers to R116-O-R 117- wherein R 116 is a cycloalkyl group and R117 is an alkylene group.
The term "cycloalkylthioalkyl" as used herein refers to R118-S-R 119- wherein R118 is a cycloalkyl group and R119 is an alkylene group.
The term "cycloalkylsulfonylalkyl" as used herein refers to
R120-S(O)2-R121- wherein R120 is a cycloalkyl group and R121 is an alkylene group.
The term "cycloalkylalkoxyalkyl" as used herein refers to
R122-O-R123- wherein R122 is a cycloalkylalkyl group and R123 is an alkylene group.
The term "cycloalkylthioalkoxyalkyl" as used herein refers to
R124-S-R125- wherein R124 is a cycloalkylalkyl group and R125 is an alkylene group.
The term "cycloalkylalkylsulfonylalkyi" as used herein refers to
R 126-S(O)2-R127- wherein R126 is a cycloalkylalkyl group and R127 is an alkylene group. The term "alkanoyl" as used herein refers to Rk-C(O)- wherein Rk is a loweralkyl group.
The term "aminocarbonyl" as used herein refers to
-C(O)NH2.
The term "aminocarbonylalkyl" as used herein refers to an aminocarbonyl group appended to a loweralkyl radical.
The term "alkylaminocarbonyl" as used herein refers to -C(O)NHR 128 wherein R128 is loweralkyl.
The term "alkylaminocarbonylalkyl" as used herein refers to an
alkylaminocarbonyl group appended to a loweralkyl radical.
The term "dialkylaminocarbonyl" as used herein refers to
-C(O)NR129R130 wherein R129 and R130 are independently selected from loweralkyl.
The term "dialkylaminocarbonylalkyl" as used herein refers to a
dialkylaminocarbonyl group appended to a loweralkyl group.
The term "aroylalkyl" as used herein refers to R131 -C(O)-R132- wherein R 131 is an aryl group and R 132 is an alkylene group.
The term "(heterocyclic)carbonylalkyl" as used herein refers to
R 133-C(O)-R134- wherein R133 is a heterocyclic group and R134 is an alkylene group.
The term "aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an amino (-NH2) group.
The term "alkylaminoalkoxy" as used herein refers to an alkoxy radical to which is appended an alkylamino group.
The term "dialkylaminoalkoxy" as used herein refers to an alkoxy radical to which is appended a dialkylamino group.
The term "(alkoxyalkyl)aminoalkyl" refers to a loweralkyl radical to which is appended an (alkoxyalkyl)amino group.
The term "(alkoxyalkyl)aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an (alkoxyalkyl)amino group.
The term "(alkoxyalkyl)(alkyl)aminoalkyl" refers to a loweralkyl radical to which is appended an (alkoxyalkyl)(alkyl)amino group. The term "(alkoxyalkyl)(alkyl)aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an (alkoxyalkyl)(alkyl)amino group.
The term "di-(alkoxyalkyl)aminoalkyl" refers to a loweralkyl radical to which is appended an di-(alkoxyalkyl)amino group.
The term "di-(alkoxyalkyl)aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an di-(alkoxyalkyl)amino group.
The term "carboxyalkoxy" as used herein refers to an alkoxy radical to which is appended a carboxy (-COOH) group.
The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (H2NC(O)-) group.
The term "alkylaminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
The term "dialkylaminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an dialkylaminocarbonyl group.
The term "(heterocyclic)carbonylalkoxy" as used herein refers to
R135-C(O)-R136-O- wherein R135 is a heterocyclic group and R136 is an alkylene group, for example, 2-(morpholin-1 -yl-carbonyl)ethoxy and the like.
The term "arylalkoxycarbonylalkyl" as used herein refers to R137-O-C(O)- R138- wherein R137 is an arylalkyi group and R138 is an alkylene group.
The term "alkanoyl" as used herein refers to R139-C(O)- wherein R139 is a loweralkyl group.
The term "aroyl" as used herein refers to R140-C(O)- wherein R140 is an aryl group.
The term "alkylsulfonyl" as used herein refers to R141-S(O)2- wherein R141 is a loweralkyl group.
The term "arylsulfonyl" as used herein refers to R142-S(O)2- wherein R142 is an aryl group.
At each occurrence, the term "heterocyclic ring" or "heterocyclic" as used herein independently refers to a 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5- membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized or N-oxidized. The sulfur heteroatoms can be optionally S-oxidized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring.
Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, tetrahydroqumolyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, thienyl and benzothienyl.
Heterocyclics also include:
Figure imgf000022_0001
Preferred heterocyclics are pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl and
tetrahydropyranyl.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (=O), alkylimino (R*N= wherein R* is a loweralkyl group), amino,
(N-protected)amino, alkylamino, (N-protected)alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, -COOH, -SO3H, loweralkenyl, loweralkyl, hydroxyalkyl, aminoalkyl and alkoxyalkyl. Heterocyclics can also be substituted with a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphoHnyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which can be unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy.
In addition, nitrogen containing heterocycles can be N-protected.
The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to
imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, furanylmethyl,
isoxazolylmethyl and the like.
The term "naturally occurring α-amino acid" as used herein refers to alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine,
glutamine, aspartic acid, glutamic acid, lysine, arginine or histidine.
In the compounds of the invention, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Most preferred compounds of the invention are selected from the group consisting of:
(5R ,6 R)-2 ,4-Bis-(4-hyd roxybe nzyl)- 1 -(3-methylbutyryl)-5-be nzyl- 6-hydroxy-3-oxo-1 ,2 ,4-triazacycloheptane;
(5 R , 6 R)-2 ,4- Bis- (3-aminobenzyl)-1 -(3-methylbutyryl)-5-benzyl-6- hydroxy-3-oxo-1 ,2,4-triazacycloheptane; and
(5R,6R)-2 ,4-Bis-(4-aminobenzyl)-1 -(3-methylbutyryl)-5-benzyl-6- hydroxy-3-oxo- 1 ,2,4-triazacycloheptane;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Compounds useful as intermediates for the preparation of the compounds of formula A include the compound of the formula C:
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000026_0001
R8 is hydrogen or an O-protecting group; and
R9 and R10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.
Preferred compounds of the formula C are those wherein R 1 is loweralkyl or arylalkyi and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
A preferred N-protecting group R9 is t-butyloxycarbonyl or
benzyloxycarbonyl.
A preferred N-protecting group R 10 is t-butyloxycarbonyl or
benzyloxycarbonyl.
More preferred compounds are compounds of the formula C wherein R1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
Even more preferred compounds of the formula C are those wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl,
di-(methoxyphenyl)methyl or triphenylmethyl.
Even more highly preferred compounds are compounds of the formula C wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
Most highly preferred compounds are compounds of the formula C wherein R1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R2 is R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl. Preferred compounds of the formula C also include compounds of the formula D:
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0001
R8 is hydrogen or an O-protecting group; and
R9 and R10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.
Preferred compounds of the formula D are those wherein R1 is loweralkyl or arylalkyl and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
A preferred N-protecting group R9 is t-butyloxycarbonyl or
benzyloxycarbonyl.
A preferred N-protecting group R10 is t-butyloxycarbonyl or
benzyloxycarbonyl.
More preferred compounds are compounds of the formula D wherein R1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl,
di-(methoxyphenyl)methyl or triphenylmethyl.
Even more preferred compounds of the formula D are those wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl,
di-(methoxyphenyl)methyl or triphenylmethyl.
Even more highly preferred compounds are compounds of the formula D wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
Most highly preferred compounds are compounds of the formula D wherein R1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl,
di-(methoxyphenyl)methyl or triphenylmethyl. Other compounds which are useful as intermediates for the preparation of the compounds of formula A include the compound of the formula E:
Figure imgf000030_0002
Figure imgf000030_0001
Figure imgf000031_0001
R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl;
R8 is hydrogen or an O-protecting group; and X is
(i) -C(=Y)- wherein Y is O, S or N(R5) wherein R5 is loweralkyl,
hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro;
(ii) -S(O)- or
(iii) -S(O)2-;
or a salt thereof.
Preferred compounds of the formula E are those wherein R1 is loweralkyl or arylalkyi; R2b is benzyl and R8 is an O-protecting group.
More preferred compounds are compounds of the formula E wherein R1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl and X is -C(=O)-.
Even more preferred compounds of the formula E are those wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl and X is -C(=O)-.
Preferred compounds of formula E also include compounds of the formula F:
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000033_0001
Figure imgf000034_0001
R8 is hydrogen or an O-protecting group; and
X is
(i) -C(=Y)- wherein Y is O, S or N(R5) wherein R5 is loweralkylO
hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro;
(ii) -S(O)- or
(iii) -S(0)2-;
or a salt thereof.
Preferred compounds of the formula F are those wherein R1 is loweralkyl or arylalkyi; R2b is benzyl and R8 is an O-protecting group.
More preferred compounds are compounds of the formula F wherein R1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl and X is -C(=O)-.
Even more preferred compounds of the formula F are those wherein R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl and X is -C(=O)-.
The compounds of the invention can be prepared as shown in Schemes 1 - 5. The schemes outline the preparation of the compounds of the invention having the preferred stereochemistry. However, other stereoisomers of the compounds of the invention can be prepared by starting with the aminoalcohol having the opposite stereochemistry to that shown for compound 1 in Scheme 1. As outlined in Scheme 1 , oxidation (for example, Swern oxidation) of
(D)-aminoalcohol 1 (R9 is an N-protecting group, for example,
benzyloxycarbonyl and R1 is defined as above) provides aldehyde 2.
Olefination (for example, by Wittig reaction) of N-protected aldehyde 2 provides olefin 3. Epoxidation of olefin 3 (for example, with m-chloroperbenzoic acid (MCPBA)) provides a mixture of epoxides 4 and 5. Separation of the epoxides (for example, by chromatography) provides the desired epoxide isomer 4.
As outlined in Scheme 2, reaction of N-protected hydrazine 6 (R10 is an N-protecting group, for example, benzyloxycarbonyl) with an aldehyde or ketone derivative of substituent R2b provides hydrazone 7. Reduction of hydrazone 7 (for example, by hydrogenation) provides hydrazine 8.
Alternatively, the appropriate hydrazine R2b-NH-NH2 can be N-protected to provide 8.
As outlined in Scheme 3, reaction of epoxide 4 with hydrazine 8 provides hydroxy hydrazine 9. Protection of the hydroxyl group with an O-protecting group (for example, trimethylsilylethoxymethyl, methoxyethoxymethyl or methoxymethyl and the like) provides 10. Removal of N-protecting groups provides 11.
As outlined in Scheme 4, reaction of 11 with Q-X-Q' (Q and Q' are activating groups and X is defined as above) provides 12. When X is -C(=O)- or -C(=S)-, Q and Q" are, for example, independently selected from imidazolyl, N-succinimidyloxy, -O-phenyl, halogen and the like. When X is -C(=N-CN)-, Q-X-Q' is, for example, MeS-C(=N-CN)-SMe and the like. When X is -S(O)- or -S(O)2-, Q and Q' are, for example, imidazolyl and the like. Compounds wherein X is -C(=N-R5)- wherein R5 is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy or benzyloxy can be prepared by reacting the appropriate amine with the corresponding cyclic thiourea.
Alkylation of 12 with R3-Z and R4-Z' wherein Z and Z' are independently selected from leaving groups, for example, a sulfonate (mesylate, tosylate, triflate and the like) or a halogen and the like, provides 13. When R3 and R4 are the same, the alkylation can be done in one step. When R3 and R4 are different, the alkylltions are done sequentially (the R4 substituent being introduced first, followed by the R3 substituent). Deprotection of the hydroxyl group then provides 14.
As outlined in Scheme 5, various substituents R2 can be introduced by first removing the N-protecting group R2b from compound 12 (by hydrogenation or other suitable N-debenzylation method) to give 13. Acylation or sulfonylation of 13 with R2-Z wherein R2-Z is a carboxylic acid halide or sulfonyl halide and the like provides 14.
Alkylation of 14 with R3-Z' and R4-Z" wherein 71 and Z" are independently selected from leaving groups, for example, a sulfonate (mesylate, tosylate, triflate and the like) or a halogen and the like, provides 15. When R3 and R4 are the same, the alkylation can be done in one step. When R3 and R4 are different, the alkylations are done sequentially (the R4 substituent being introduced first, followed by the R3 substituent). Deprotection of the hydroxyl group then provides 16.
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
The following examples will serve to further illustrate the preparation of the novel compounds of the invention. Example 1
A. N-((Benzyloxy)carbonyl)-D-Dhenylalaninal.
To a solution of 1.8 ml of dimethyl sulfoxide in 20 ml of dichloromethane cooled to -78°C was added slowly 1.65 ml of oxalyl chloride. The solution was stirred for 10 min at -78°C and a solution of 3.6 g (0.012 mole) of
N-((benzyloxy)carbonyl)-D-phenylalaninol in 45 ml of dichloromethane was added slowly. The resulting solution was stirred at -78°C for 15 min, then 1 min at 0°C; recooling to -78°C and 7.6 ml of triethylamine was added over 10 min. After stirring at -78°C for 25 min, 20 ml of cold 10% aq. citric acid solution was added. After warming to 0°C, 200 ml of ether and 55 ml of cold 10% citric acid were added. The organic layer was separated by separatory funnel and washed repeatedly (5 x 60 ml) with water and finally with satd. NaCl solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo at RT to give 3.51 g of the desired
compound as an off-white solid.
B. N(( Benzyloxytearbonyl)-2R-amino-1-phenyl-but-3-ene.
To a dry 250 ml 3-neck flask was added 14.34 g of
triphenylmethylphosphonium bromide. To this was added 70 ml of THF, cooled to 0°C and 4.42 g of 35% potassium hydride dispersion in oil was added. The mixture was stirred at RT for 24 h. To this mixture was added 30 ml of toluene and let stand for 30 min. The supernatant was cannulated over into a solution of 3.37 g of N-((benzyloxy)carbonyl)-D-phenylalaninal in 50 ml of toluene at -78°C. The reaction mixture was stirred at -78°C for 2 h, followed by 0.5 h at RT. Satd. ammonium chloride (50 ml) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with satd. NaCl solution and dried over anhydrous sodium sulfate, filtered and concentrated to a yellow oil which was purified by silica gel column chromatography (30% ether/hexane) to provide 3.02 g (89%) of desired compound as a white solid. 1 H NMR (CDCI3):
δ 2.88 (d, 2H), 4.50 (m, 1 H), 4.70 (m, 1 H), 5.10 (m, 3H), 5.80 (m, 1 H), 7.10- 7.40 (m, 10H). Mass spectrum: (M+1)+ = 282. C. N-((Benzyloxy)carbonyl)-2R-amino-3S-3,4-epoxybutane.
According to the procedure of Luly, et al. (J. Org. Chem.52, 1487 (1987)), to a solution of 2.97 g of the product of Example 1 B in 75 ml of
dichloromethane at 0°C was added 9 g of MCPBA. The solution was stirred at 0°C for 1 h and then at RT overnight. It was added to 250 ml of ether and washed successively with cold 10% sodium thiosulfate, 10% sodium carbonate and then satd. NaCl solution. The organic layer was dried and concentrated to a colorless oil which was purified by silica gel column chromatography (20% EtOAc/hexane) to provide 2.7 g of the desired product containing a small amount of the 3R diastereomer. 1 H NMR (CDCI3): 5 2.57 (m, 1 H), 2.70 (t,
J=4.5 Hz, 1 H), 2.90 - 3.05 (m, 1 H), 4.20 (m, 1 H), 4.70 (br d, 1 H), 7.20- 7.38 (m, 10H). Mass spectrum: (M+H)+ = 298.
D. N(1) -Benzyloxycarbonyl-N(2)-benzyl hydrazine,
To a solution of 5 g of benzylhydrazine dihydrochloride in 50 ml of THF was added 5.9 ml of N-methylmorpholine and 7.6 g of CBz-NOS at 0°C. After 1 h, the reaction mixture was warmed to RT and stirred at RT overnight. After filtering off the solid formed and concentration of the filtrate; silica gel column chromatography (10% acetone/90% hexane) provided 2.6 g of desired product. 1 H NMR (CDCI3): δ 3.25 (br s, 1 H), 4.05 (s, 2H), 5.16 (s, 2H), 6.23 (br s, 1 H), 7.25 (m, 10H). E. 2-(Benzyloxycarbonyl)amino-4R-hydroxy-5R-
(benzyloxycarbo nyl)amino-1 ,6-di phenyl-2-azahexane,
To a solution of 1.2 g of the product of Example 1 C in 36 ml of isopropanol was added 1.03 g of the hydrazine from Example 1 D. The solution was heated at reflux for 24 h; cooled to RT and concentrated in vacuo. Silica gel column chromatography (10% to 20% acetone/hexane) provided 1.5 g of desired product. 1 H NMR (CDCI3): δ 2.55 (m, 1 H), 2.80 (m, 1 H), 2.95 (d, 2H), 3.60 (m, 2H), 3.70 - 4.00 (m, 3H), 4.30 (s, 1 H), 5.03 (s, 2H), 5.05 (s, 2H), 5.30 (m, 1 H), 5.48 (s, 1 H), 7.30 (m, 20H). F. 2-(benzyloxycarbonyl)amino-4R-(trimethylsilyl-ethoxy-methoxy)- 5R-(benzyloxycarbonyl)amino-1 ,6-diphenyl-2-azahexane.
To a solution of the product from Example 1 E in 12 ml of
dimethylformamide was added 1.8 ml of diisopropyl ethyl amine and then 1.14 ml of trimethylsilyl ethoxymethyl chloride. The reaction mixture was stirred at RT for 19 h. The DMF was removed in vacua. The residue was extracted with EtOAc (3 x 80 ml) and washed with satd. NaCl solution. The organic layer was dried with anhy. sodium sulfate, filtered and the solvent evaporated in vacuo. Purification of the residue by silica gel column chromatography
(20% acetone/hexane) provided 1.23 g (83%) of the desired compound.
1 H NMR (CDCI3): δ 0.1 (s, 9H), 0.95 (t, 2H), 2.80 (m, 3H), 3.10 (m, 1 H), 3.65 (m, 3H), 3.97 (m, 1 H), 4.26 (m, 1 H), 4.70 (m, 2H), 5.00 (m, 4H), 5.30 (m, 1 H), 7.25 (m, 20H).
G. 2-Amino-4R-(trimethylsilyl-ethoxymethoxy)-5R-amino-1 ,6- diphenyl-2-azahexane.
To a suspension of 100 mg of 10% Pd/C in 20 ml of methanol was added 1.2 g of the product from Example 1 F. The mixture was stirred
vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 0.70 g of crude product. 1 H NMR (CDCI3): δ 0.2 (s, 9H), 0.95 (t, 2H),
2.10 (m, 4H), 2.70 (m, 2H), 2.90 (m, 2H), 3.39 (m, 1 H), 3.70 (m, 4H), 3.90 (m, 1 H), 4.80 (m, 2H), 7.30 (m, 10H).
H. (5R,6R)-1 ,5-Dibenzyl-3-oxo-6-(trimethylsilylethoxy-methoxy)-
1 ,2,4-triazacycloheptane.
To 120 ml of dichloromethane with stirring was added 300 mg of carbonyldiimidazole (in 5 ml of CH2CI2) and 0.7 g of the product of
Example 1 G (in 5 ml of CH2CI2) over a period of 2 h via a syringe pump. The solution was kept at RT for 72 h; concentration in vacuo and purification by silica gel column chromatography (20% EtOAc/CH2Cl2) provided 400 mg of desired compound. 1 H NMR (CDCI3): δ 0.20 (s, 9H), 0.90 (t, 2H), 2.96 (m,
2H), 3.17 (m, 2H), 3.70 (m, 3H), 4.10 (m, 3H), 5.52 (br s, 1 H), 4.75 (m, 2H),
5.70 (br s, 1 H), 7.30 (m, 10H). I. (5R,6R)-5-benzyl-6-(trimethylsilylethoxymethoxy)-3- oxo-1,2,4-triazacycIoheptane.
To a suspension of 72 mg of 20% palladium hydroxide on carbon in 36 ml of methanol was added 360 mg of the product of Example 1H. The mixture was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 285.0 mg of the desired product. 1H NMR (CDCI3) δ 0.01 (s, 9H), 0.92 (m, 2H), 2.92 (m, 3H), 3.33 (dd, 1H), 3.57-3.70 (m, 4H), 4.17 (br d, 1H), 4.32 (br s, 1H), 4.87 (dd, 2H), 5.95 (br s, 1H), 7.18-7.33 (m, 5H). Mass spectrum: (M+H)+ = 352.
J. (5R,6R)-1-benzoyl-5-benzyl-6-(trimethylsilylethoxy- methoxy)-3-oxo-1,2,4-triazacycloheptane.
To a solution of 88 mg (0.25 mmol) of the product of Example 11 in 10 ml of CH2CI2 was added 24.0 μl (0.30 mmol) of anhydrous pyridine and 32.0 μl (0.28 mmol) of benzoyl chloride. After being stirred at RT for 0.5 h, the mixture was treated with 2 ml of water, extracted with CH2CI2 (4 X 5 ml). The combined organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 5% MeOH in
CH2CI2, provided 108.4 mg (95%) of desired product. Mass spectrum: (M+H)+ = 456.
K. (5R,6R)-2,4-Bis-(2-propen-1-yh-1-benzoyl-5-benzyl- 6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Figure imgf000043_0001
To a suspension of 71 mg (2.4 mmol) of NaH (80% oil
dispersion) in 0.5 ml of DMF was added a solution of 108.0 mg (0.24 mmol) of the product of Example 1J in 1.5 ml of DMF. After stirring at RT for 30 min, 123 μl (1.4 mmol) of allyl bromide was added. The reaction mixture was stirred at RT for 1h and quenched at 0°C with 5 ml of satd. NH4CI solution and extracted with CH2CI2 (4 X 5 ml). The combined CH2CI2 solution was washed with brine and dried.
Concentration in vacuo and purification by silica gel column
chromatography using 25% EtOAc in hexane, provided 110.4 mg of product. It was then deprotected by dissolving in 5 ml of MeOH, stirred with 125 μl of trimethylsilyl chloride at RT for 4 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 5% MeOH in CH2CI2, provided 81.4 mg (85%) of desired product. Mass spectrum: (M+H)+ = 406.
L. (5R,6R)-2,4-Bis-(1-propyn-1-benzoyl-5-benzyl-6- hydroxy-3-oxo-1,2,4-triazacycloheptane.
To a suspension of 25 mg of 10% Pd/C in 10 ml of EtOAc was added 50 mg of the product of Example 1K. The reaction mixture was stirred vigorously under a hydrogen atmosphere (hydrogen filled balloon) for 1.5 h. Filtration, concentration in vacuo and purification by silica gel column chromatography using 50% EtOAc in hexane provided 45.4 mg (90%) of desired product as a white foam. 1H NMR (CDCl3) δ 0.69-1.10 (six t, 6H), 1.24-1.45 (m, 2H), 1.55-2.01 (m, 2H), 2.42-2.93 (m, 1H), 3.00-3.28 (m, 3H), 3.33-3.54 (m, 2H), 3.60-3.72 (m, 2H), 3.92-4.13 (m, 2H), 4.26-4.86 (m, 1H), 7.17-7.55 (m, 10H). Mass spectrum: (M+H)+ = 410.
Example 2
A. (5R,6R)-1-acetyl-5-benzyl-6-(trimethylsilylethoxy- methoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with the acetyl chloride, provided the desired compound. 1H NMR (CDCI3) δ 0.04 (s, 9H), 0.95 (m, 2H), 2.19 (s, 3H), 2.79 (dd, 1H), 2.96 (m, 1H), 3.69 (m, 4H), 4.04 (m, 1H), 4.40 (br s, 1H), 4.70 (d, 1H), 4.83 (dd, 1H), 4.85 (d, 1H), 6.84 (s, 1H), 7.18-7.39 (m, 5H). Mass spectrum: (M+H)+ = 394.
B. (5R,6R)-2,4-Bis-(2-propen-1-yl)-1-acetyl-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Exampl 1J with the product of Example 2A , provided the desired compound. 1Η NMR (CDCI3) δ 1.99 (s, 3H), 2.33 (d, 1H), 2.48 (dd, 1H), 2.80 (dd, 1H), 2.98 (dd, 1H), 3.15 (dd, 1H), 3.43 (dt, 1H), 3.73 (dd, 1H), 3.95 (m, 1H), 4.06 (ddt, 1H), 4.47 (dd, 1H), 4.69 (dd, 1H), 4.88 (d, 1H), 5.00 (d, 1H), 5.32 (d, 1H), 5.39 (d, 1H), 5.47 (m, 1H), 6.04 (m, 1H), 7.18-7.34 (m, 5H). Mass spectrum: (M+H)+ = 344.
C. (5R,6R)-2,4-Bis-(1-Dropyl)-1-acetyl-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 2B, provided the desired compound. 1H NMR (CDCI3) δ 0.68 (t, 3H), 1.02 (t, 3H), 1.21 (m, 2H), 1.77 (q, 2H), 1.91 (m, 1H), 2.00 (s, 3H), 2.86 (dd, 1H), 2.98-3.07 (m, 3H), 3.14 (dd, 1H), 3.39 (dt, 1H), 3.50 (m, 1H), 3.98 (m, 1H), 4.07 (m, 1H), 4.53 (dd, 1H), 7.19-7.32 (m, 5H). Mass spectrum: (M+H)+ = 348.
Anal. Calcd. for C19H29N3O3O.5H2O: C, 64.84; H, 8.45; N, 11.94; Found: C, 64.73; H, 8.23; N, 11.70.
Example 3
A. (5R,6R)-1-propionyl-5-benzyl-6-(trimethylsilyl- ethoxy-methoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example U, but replacing the benzoyl chloride with propionyl chloride, provided the desired compound.
Mass spectrum: (M+H)+ = 448. B. (5R,6R)-2,4-Bis-(2-propen-1-yl)-1-propionyl-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product from Example 3A, provided the desired compound. Mass spectrum: (M+H)+ = 358.
C. (5R,6R)-2,4-Bis-(1-propyn-1-propionyl-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 3B, provided the desired compound. 1H NMR (CDCI3) δ 0.66 (t, 3H), 1.03 (t, 3H), 1.08 (t, 3H), 1.14-1.27 (m, 2H), 1.76 (m, 2H), 1.82 (ddd, 1H), 2.23 (m, 1H), 2.33 (m, 2H), 2.86 (dd, 1H), 3.00 (m, 1H), 3.13 (dd, 2H), 3.37 (dt, 1H), 3.48 (dt, 1H). 3.96-4.03 (m, 1H), 4.06-4.12 (m, 1H), 4.54 (dd, 1H), 7.19-7.34 (m, 5H). Mass spectrum: (M+H)+ = 362.
Anal. Calcd. for C20H31N3O3: C, 66.45; H, 8.64; N, 11.62; Found: C, 66.36; H, 8.61; N, 11.55.
Example 4
A. (5R,6R)-1-(2-methylpropionyl)-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1J, but replacing the benzoyl chloride with isobutyryl chloride, provided the desired compound. 1 H NMR (CDCI3) δ 0.03 (s, 9H), 0.96 (t, 2H), 1.12 (d, 6H), 2.79 (m, 1H), 2.94 (m, 1H), 3.11 (m, 1H), 3.21 (m, 1H), 3.70 (m, 3H), 4.08 (m, 1H), 4.41 (br s, 1H), 4.71 (d, 1H), 4.77 (m, 1H), 4.85 (d, 1H), 6.74 (br s, 1H), 7.18 (m, 2H), 7.25-7.35 (m, 3H). Mass spectrum: (M+H)+ = 422. B. (5R,6R)-2,4-Bis-(2-propen-1-yl)-1-(2- methylpropionyl)-5-benzyl-6-hydroxy-3-oxo-1 ,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 4A, provided the desired compound.
C. (5R,6R)-2,4-Bis-(1-propyn-1-(2-methylpropionyl)-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 4B , provided the desired compound. 1H NMR (CDCI3) δθ.65 (t, 3H), 0.99 (d, 3H), 1.03 (t, 3H), 1.14 (d, 3H),1.22 (m, 2H), 1.78 (m, 2H), 1.91 (m, 1H), 2.74 (m, 1H), 2.88 (dd, 1H), 3.03 (m, 3H), 3.15 (m, 1H), 3.41 (m, 1H), 3.92 (m, 1H), 4.06 (ddd, 1H), 4.58 (dd, 1H), 7.19-7.33 (m, 5H). Mass spectrum:
(M+H)+ = 376.
Anal. Calcd. for C21H33N3O3: C, 67.17; H, 8.86; N, 11.19; Found: C, 67.29; H, 9.14; N, 11.15.
Example 5
A. (5R,6R)-1-(2,2-dimethylpropionyl)-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1J, but replacing the benzoyl chloride with pivaloyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 436.
B. (5R,6R)-2,4-Bis-(2-propen-1-yl)-1-(2,2- dimethylpropionyl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 5A, provided the desired compound. C. (5R,6R)-2,4-Bis-(1-propyn-1-(2,2-dimethyl- propionyl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 5B, provided the desired compound. Mass spectrum: (M+H)+ = 390.
Anal. Calcd. for C22H35N3O3: C, 67.83; H, 9.06; N, 10.79; Found: C, 67.73; H, 9.19; N, 10.66.
Example 6
A. (5R,6R)-1-methanesulfonyl-5-benzyl-6-(trimethyl- silyl-ethoxymethoxy)-3-oxo-1,2,4-triazacycloheptane.
To a solution of 100 mg (0.28 mmol) of the product of Example 11 in 5 ml of CH2CI2 was added 95.2 μl (0.68 mmol) of triethylamine and 48.4 μl (0.64 mmol) of methanesulfonyl chloride. The mixture was stirred at 0°C for 2 h and then at RT for 5 h. Evaporated the solvent. The residue was purified by silica gel column
chromatography using 70% EtOAc in hexane, provided 68.6 mg (57%) of desired product. 1H NMR (CDCI3) δ 0.04 (s, 9H), 0.97 (m, 2H), 2.89 (dd, 1H), 3.00 (dd, 1H), 3.14 (s, 3H), 3.36 (br d, 1H), 3.64-3.85 (m, 4H), 4.35 (br d, 1H), 4.38 (br s, 1H), 4.74 (d, 1H), 4.88 (d, 1H), 6.57 (d, 1H), 7.20-7.28 (m, 5H). Mass spectrum: (M+H)+ = 430.
B. (5R,6R)-2,4-Bis-(2-propen-1-yl)-1-methane- sulfonyl-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product from Example 1J with the product from Example 6A, provided the desired compound. 1H NMR (CDCI3) 1.93 (d, 1H), 2.58 (dd, 1H), 2.88 (dd, 1H), 3.00 (s, 3H), 3.09 (dd, 1H), 3.25 (dd, 1H), 3.47 (dt, 1H), 3.96 (m, 2H), 4.14 (m, 2H), 4.58 (dd, 1H), 4.94 (d, 1H), 5.03 (d, 1H), 5.33 (d, 1H), 5.39 (d, 1H), 5.56 (m, 1H), 6.04 (m, 1H), 7.15-7.32 (m, 5H). Mass spectrum: (M+H)+ = 380.
Anal. Calcd. for C18H25N3O4S: C, 56.97; H, 6.64; N, 11.07; Found: C, 56.93; H, 6.73; N, 10.94.
Example 7
A. (5R,6R)-1-bromoacetyl-5-benzyl-6-(trimethylsilyl- ethoxy-methoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with the bromoacetyl chloride, provided the desired
compound. 1H NMR (CDCI3) δ 0.03 (s, 9H), 0.95 (m, 2H), 2.79 (dd, 1H), 2.94 (m, 1H), 3.73 (m, 4H), 4.06 (m, 1H), 4.23 (br s, 2H), 4.49 (br s, 1H), 4.71 (m, 2H), 4.86 (br d, 1H), 7.18-7.39 (m, 6H). Mass spectrum: (M+NH4)+ = 491, 489.
B. (5R,6R)-1-(N,N-dimethylglycyl)-5-benzyl-6- (trimethylsilylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
To a solution of 60 mg (0.13 mmol) of the product of Example 7A in 3 ml of CH2CI2 was added 0.5 ml (0.64 mmol) of 1.3 M
dimethylamine in ether. The mixture was stirred at RT for 2 h and then treated with 3 ml of water, extracted with CH2CI2 (4 X 5 ml). The combined organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column
chromatography using 10% MeOH in CH2CI2, provided 55.4 mg (100%) of desired product. 1H NMR (CDCI3) δ0.03 (s, 9H), 0.97 (m, 2H), 2.32 (s, 6H), 2.88 (dd, 1H), 3.00 (dd, 1H), 3.09 (m, 1H), 3.27 (m, 1H), 3.67 (m, 2H), 3.79 (m, 2H), 3.92 (br s, 1H), 4.14 (br s, 1H), 4.40 (br s, 1H), 4.73 (d, 1H), 4.91 (d, 1H), 7.19-7.37 (m, 5H), 8.94 (br s, 1H). Mass spectrum: (M+H)+ = 437. C. (5R,6R)-2,4-Bis-cyclopropylmethyl-1-(N,N- dimethylglycyl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1L, but replacing the product from Example 1K with the product of Example 7B and replacing the allyl bromide with bromomethyl cyclopropane, provided the desired compound. 1H NMR (CDCI3) δ0.36 (m, 4H), 0.67 (m, 4H), 1.12 (m, 1H), 1.87 (dd, 1H), 2.32 (s, 6H), 2.86 (dd, 1H), 2.91-3.34 (m, 8H), 3.57 (m, 1H), 3.79 (m, 1H), 3.95 (dd, 1H), 4.07 (m, 1H), 4.55 (dd, 1H), 7.20-7.33 (m, 5H). Mass spectrum: (M+H)+ = 415.
Example 8
A. (5R,6R)-1-(2-furoyl)-5-benzyl-6-(trimethylsilyl- ethoxymethoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with 2-furoyl chloride, provided the desired compound.
Mass spectrum: (M+H)+ = 446.
B. (5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(2-fur0yl)-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 8A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 528.
Anal. Calcd. for C30H29N3O6.0.5H2O: C, 67.15; H, 5.64; N, 7.83; Found: C, 66.99; H, 5.49; N, 7.74.
Example 9
(5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-acetyl-5-benzyl-6- hydroxy- 3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 2A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1 H NMR (DMSO-D6) (mixture of three rotamers) δ 1.83, 1.87 and 2.03 (three s, 3H), 2.33-2.45 (m, 1H), 2.60 (m, 1H), 2.73 (m, 1H), 2.83 (m, 1H), 3.13-3.23 (m, 1H), 3.55-3.68 (m, 1H), 3.95, 4.17 and 4.25 (three d, 1H), 4.28, 4.36 and 4.55 (three d, 1H), 4.89, 4.92 and 4.96 (three d, 1H), 5.36, 5.38 and 5.48 ( three d, 1H), 6.63 (m, 4H), 6.78 (m, 2H), 7.02 (m, 2H), 7.17-7.34 (m, 5H), 9.29, 9.34, 9.35, 9.39, 9.47 and 9.52 (six s, 2H). Mass spectrum: (M+H)+ = 528.
Anal. Calcd. for C27H29N3O5.0.75H2O: C, 66.31; H, 6.29; N, 8.59; Found: C, 66.35; H, 6.16; N, 8.59.
Example 10
(5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(2-methyl- propionyl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 4A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-d6) (mixture of three rotamers) 0.86-1.09 (six d, 3H), 2.33-2.46, (m, 1H), 2.66-3.03 (m, 4H), 3.24 (m, 1H), 3.42-3.78 (three m, 1H), 3.98-4.08 (m, 1H), 4.28, 4.46 and 4.60 (three d, 1H), 4.81, 4.83 and 5.03 (three d, 1H), 5.12, 5.16 and 5.28 (three d, 1H), 6.60-6.80 (m, 6H), 6.98-7.33 (m, 7H), 9.03-9.23 (six s, 2H). Mass spectrum: (M+H)+ = 521.
Anal. Calcd. for C29H33N3O50.5H2O: C, 67.95; H, 6.69; N, 8.20; Found: C, 67.87; H, 6.60; N, 8.11.
Example 11
A. (5R,6R)-1-(butyryl)-5-benzyl-6-(trimethylsilyl- ethoxy-methoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with butyryl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 422. B. (5R,6R)-2,4-Bis-(4-hydroxybenzyh-1-(butyryl)-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 11 A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-d6) (mixture of three rotamers) 0.81 and 0.94 (three t, 3H), 1.44-1.57, (m, 2H), 2.34-2.67 (m, 1H), 2.73-2.97 (m, 2H), 3.22 (m, 1H), 3.63-3.72 (m, 1H), 3.98 (m, 1H), 4.12-4.23 (m, 1H), 4.22-4.56 (three d, 1H), 4.85-4.98 (three d, 1H), 5.33-5.47 (three d, 1H), 6.60-6.79 (m, 6H), 6.98-7.35 (m, 7H), 9.33 (br s, 1H), 9.46 (br s, 1H). Mass spectrum: (M+H)+ = 504.
Example 12
A. (5R,6R)-1-(3-methylbutyryl)-5-benzyl-6- (trimethylsilyl-ethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with isovaleryl chloride, provided the desired compound. 1 H NMR (CDCI3) δ 0.03 (s, 9H), 0.96 (m, 8H), 2.15 (m, 1H), 2.36 (m, 2H), 2.77 (m, 1H), 2.95 (m, 1H), 3.71 (m, 3H), 4.06 (m, 1H), 4.36 (br s, 1H), 4.72 (d, 1H), 4.81 (m, 1H), 4.87 (d, 1H), 6.50 (br s, 1H), 7.16-7.35 (m, 5H). Mass spectrum: (M+H)+ = 436.
B. (5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(3- methylbutyryl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-d6) (mixture of three rotamers) 0.81-0.95 (four d, 6H), 1.72-2.45 (m, 4H), 2.56-2.86 (m, 1H), 3.03-3.25 (m, 1H), 3.63 (m, 1H), 4.18 (m, 1H), 4.25, 4.38 and 4.53 (three d, 1H), 4.94 (m, 1H), 5.33, 5.38 and 5.46 (three d, 1H), 6.61- 6.79 (m, 6H), 6.98-7.32 (m, 7H), 9.33, 9.39 and 9.47 (three br s, 2H). Mass spectrum: (M+H)+ = 518.
Example 13
A. (5 R,6R)-1-valeryl-5-benzyl-6-(trimethyisilyl- ethoxy-methoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with valeryl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 436.
B. (5R,6R)-2,4-Bis-(4-hydroxybenzyn-1-valeryl-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacvcloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 13A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1 H NMR (DMSO-D6) (mixture of three rotamers) δθ.81, 0.87 and 0.92 (three t, 3H), 1.19, 1.37 and 1.52 ( three m, 4H), 1.90, 2.13 and 1.32 (three m, 2H), 2.39 (m, 1H), 2.62- 2.97 (m, 3H), 3.07-3.22 (m, 1H), 3.60-3.65 (m, 1H), 3.92, 3.96 and 4.03 (three d, 1H), 3.97, 4.16 and 4.21 (three d, 1H), 4.29, 4.38 and 4.52 (three d, 1H), 4.83, 4.89 and 4.95 (three d, 1H), 5.35, 5.38 and 5.47 (three d, 1H), 6.61 (m, 4H), 6.76 (m, 2H), 7.03(m, 2H), 7.16-7.33 (m, 5H), 9.30, 9.35, 9.39 and 9.47 (four br s, 2H). Mass spectrum:
(M+H)+ = 518.
Anal. Calcd. for C30H35N3O50.5H2O: C, 68.42; H, 6.89; N, 7.98; Found: C, 68.54; H, 6.79; N, 7.72. Example 14
A. (5R,6R)-1-(2-ethylbutyryl)-5-benzyl-6-(trimethyl- silyl-ethoxymethoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with 2-ethylbutyryl chloride, provided the desired
compound. Mass spectrum: (M+H)+ = 450.
B. (5R,6R)-2,4-Bis-(4-hydroxybenzyn-1-(2-ethyl- butyryl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 14A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-D6) (mixtures of three rotamers) δ 0.75-0.96 (three m, 6H), 1.25-1.58 (three m, 4H), 2.36-2.46 (m, 1H), 2.65-2.85 (m, 3H), 3.15-3.25 (m, 2H), 3.68 (m, 1H), 3.95 (d, 1H), 4.10 (m, 1H), 4.38 (d, 1H), 4.95, 5.06 and 5.13 (three d, 1H), 5.38, 5.40 and 5.44 (three d, 1H), 6.57-6.63 (m, 4H), 6.87 (dd, 2H), 6.90 (dd, 1H), 7.12 (dd, 1H), 7.22-7.32 (m, 5H), 9.28, 9.32, 9.38, 9.40, 9.48 and 9.51 ( six s, 2H). Mass spectrum: (M+NH4)+ = 549.
Anal. Calcd. for C31H37N3O50.5H2O: C, 68.87; H, 7.08; N, 7.77; Found: C, 68.88; H, 7.09; N, 7.68.
Example 15
A. (5R,6R)-1-(2-(1-propylvaleryl))-5-benzyl-6- (trimethylsilyl-ethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with 2-(1-propylvaleryl) chloride, provided the desired compound. Mass spectrum: (M+H)+ = 478. B. (5R,6R)-2,4-Bis-(4-hydroxybenzyn-1-(2-(1- propylvaleryl))-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 15A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-D6) (mixtures of three rotamers) δ 0.72, 0.85 and 0.87 (three t, 6H), 1.18-1.57 (m, 8H), 2.28-2.38 (m, 1H), 2.58-3.18 (m, 5H), 3.67 (dd, 1H), 3.97 (d, 1H), 4.03, 4.07 and 4.11 (three d, 1H), 4.12, 4.37 and 4.58 (three d, 1H), 4.94, 5.08 and 5.15 (three d, 1H), 5.35, 5.40 and 5.42 (three d, 1H), 6.52-6.63 (m, 4H), 6.74-6.79 (m, 2H), 6.87 (m, 1H), 7.09-7.16(m, 2H), 7.23-7.36 (m, 4H), 9.26, 9.31, 9.36, 9.37, 9.46 and 9.48 (six s, 2H). Mass spectrum: (M+NH4)+ = 577.
Anal. Calcd. for C33H41N3O5.0.5H2O: C, 69.69; H, 7.44; N, 7.39; Found: C, 69.95; H, 7.37; N, 7.31.
Example 16
A. (5R,6R)-1-cyclopentanecarbonyl-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with cyclopentanecarbonyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 448.
B. (5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-cyclopentane- carbonyl-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 16A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-D6) (mixtures of three rotamers) δ 1.94-1.85 (m, 8H), 2.23-2.30 (m, 1H), 2.61-3.18 (m, 5H), 3.66 (d, 1H), 3.98, 4.01 and 4.03 (three d, 1H), 4.08, 4.17 and 4.22 (three d, 1H), 4.30, 4.42 and 4.57 (three d, 1H), 4.82, 4.84 and 5.01 (three d, 1H), 5.31, 5.35 and 5.46 (three d, 1H), 6.58-6.66 (m, 4H), 6.73-6.79 (m, 2H), 6.97-6.99 (m, 1H), 7.09-7.15 (m, 2H), 7.19- 7.34 (m, 4H), 9.29, 9.34, 9.37 and 9.45 (four br s, 2H). Mass
spectrum: (M+NH4)+ = 547.
Anal. Calcd. for C31H35N3O5.0.75H2O: C, 68.55; H, 6.77; N, 7.74; Found: C, 68.51; H, 6.47; N, 7.52.
Example 17
(5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(N,N- dimethylglycyl) -5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 7B and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-d6) (mixture of three rotamers) 2.17 (s, 3H), 2.22, (s, 3H), 2.27-2.44 (m, 1H), 2.55-3.03 (m, 5H), 3.18 (m, 1H), 3.78-4.00 (m, 2H), 4.23 (m, 1H), 4.33-4.41 (m, 1H), 4.92 (m, 1H), 5.32, 5.39 and 5.50 (three d, 1H), 6.57-6.66 (m, 4H), 6.76 (m, 2H), 7.03 (m, 2H), 7.17-7.32 (m, 5H), 9.28-9.52 (six s, 2H). Mass spectrum: (M+H)+ = 519.
Example 18
A. (5R,6R)-1-(4-morpholinylacetyl)-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 7B, but replacing the
dimethylamine with morpholine, provided the desired compound.
Mass spectrum: (M+NH4)+ = 479. B. (5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(4- morpholinylacetyl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 18A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-d6) (mixture of three rotamers) 2.37-2.47 (m, 5H), 2.63-3.14 (m, 5H), 3.24 (m, 1H), 3.47- 3.59 (m, 2H), 3.82 (m, 1H), 4.00 (m, 1H), 4.25 (m, 1H), 4.34-4.43 (m, 1H), 4.91 (m, 1H), 5.32, 5.40, 5.47 (three d, 1H), 6.58-6.77 (m, 6H), 7.01-7.34 (m, 7H), 9.29-9.51 (six s, 2H). Mass spectrum: (M+H)+ = 561.
Anal. Calcd. for C31H36N4O6.0.75H2O: C, 64.85; H, 6.58; N, 9.76; Found: C, 64.58; H, 6.47; N, 9.61.
Example 19
A. (5R,6R)-1-methoxyacetyl-5-benzyl-6-(trimethyl- silyl-ethoxymethoxy)-3-oxo-1,2,4-triazacycloheptane. Using the procedure of Example 1J , but replacing the benzoyl chloride with methoxyacetyl chloride, provided the desired
compound. 1H NMR (CDCI3) δ 0.04 (s, 9H), 0.95 (m, 2H), 2.80 (dd, 1H), 2.96 (dd, 1H), 3.45 (s, 3H), 3.66-3.76 (m, 3H), 4.03 (m, 1H), 4.20 (dd, 2H), 4.41 (s, 1H), 4.72 (d, 1H), 4.88 (d, 1H), 6.95 (br s, 1H), 7.18-7.36 (m, 5H). Mass spectrum: (M+H)+ = 441.
B. (5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-methoxy- acetyl-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 19A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 523.
Anal. Calcd. for C28H31N3O6.0.75H2O: C, 64.79; H, 6.31; N, 8.09; Found: C, 64.99; H, 6.16; N, 8.00. Example 20
A. (5R,6R)-1-(t-butoxycarbonyl)-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
To a solution of 50 mg (0.14 mmol) of the product of Example 1| in 3 ml of CH2CI2 was added 46.6 mg of di-tert-butyl dicarbonate, 4 mg of DMAP and 40 μl of triethylamine. The mixture was stirred at RT for 20 h and then treated with 3 ml of water, extracted with CH2CI2 (5 X 5 ml). The combined organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 50% EtOAc in hexane, provided 53.7 mg (84%) of desired product. Mass spectrum: (M+H)+ = 452.
B. (5R,6R)-2,4-Bis-(4-hydroxybenzyn-1-(t- butoxycarbonyl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 20A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 534.
Example 21
A. (5R,6R)-1-(4-methoxycarbonylbutyryl)-5- benzyl-6-(trimethylsilylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1J , but replacing the benzoyl chloride with methyl glutaryl chloride, provided the desired
compound. Mass spectrum: (M+NH)+ = 480. B. (5R,6R)-1-(5-hydroxyvaleryl)-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
To a solution of 261.3 mg (0.54 mmol) of the product of Example 21 A in 30 ml of THF was added 1.6 ml of LiBH4 (2.0 M in THF). The mixture was stirred at RT for 20 h. It was then treated with 10 ml of 10% citric acid solution at OºC and extracted with CH2CI2 (5 x 20 ml). The combined organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 5% MeOH in CH2CI2, provided 164.5 mg (67%) of desired product. Mass spectrum: (M+NH)+ = 452.
C. (5R,6R)-1-(5-trimethylsilylethoxymethoxy- valeryn-5-benzyl-6-(trimethylsilylethoxymethoxy)- 3-oxo-1,2,4-triazacycloheptane.
Using the procedure of 1F, but replacing the product of Example 1E with the product of Example 21 B, provided the desired compound. Mass spectrum: (M+NH)+ = 582.
D. (5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(5- hydroxyvaleryl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triagacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 21 C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-D6) (mixtures of three rotamers) δ 1.34-1.61 (m, 4H), 2.07-2.47 (m, 2H), 2.55-2.96 (m, 3H), 3.16-3.24 (m, 3H), 3.38-3.46 (m, 1H), 3.60-3.65 (m, 1H), 3.94- 4.02 (m, 1H), 4.09, 4.10 and 4.12 (three d, 1H), 4.15, 4.23 and 4.25 (three d, 1H), 4.37, 4.40 and 4.46 (three t, 1H), 4.54, 4.90 and 4.97 (three d, 1H), 5.34, 5.37 and 5.46 (three d, 1H), 6.60-6.62 (m, 4H), 6.75-6.78 (m, 2H), 6.98-7.10 (m, 2H), 7.17-7.32 (m, 5H), 9.28, 9.32, 9.34, 9.38, 9.46 and 9.49 (six s, 2H). Mass spectrum: (M+H)+ = 534. Anal. Calcd. for C30H35N3O6 H2O: C, 65.32; H, 6.76; N, 7.62;
Found: C, 65.46; H, 6.62; N, 7.46.
Example 22
A. (5R,6R)-1-(3-ethoxycarbonylpropionyl)-5- benzyl-6-(trimethylsilylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of 1J, but replacing the benzoyl chloride with ethyl succinyl chloride, provided the desired compound. Mass spectrum: (M+NH)+ = 480.
B. (5R,6R)-1-(4-hydroxybutyryl)-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1,2,4- triazacvcloheptane.
Using the procedure of 21 A, but replacing the product of
Example 21 A with the product of Example 22A, provided the desired compound. Mass spectrum: (M+NH)+ = 438.
C. (5R,6R)-1-(4-trimethylsilylethoxymethoxy- butyryl)-5-benzyl-6-(trimethylsilylethoxymethoxy)- 3-oxo-1,2,4-triazacvclo heptane.
Using the procedure of Example 1F, but replacing the product of Example 1E with the product of Example 22B, provided the desired compound. Mass spectrum: (M+NH)+ = 568.
D. (5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(4- hydroxybutyryl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 22C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-D6) (mixture of three rotamers) δ 1.57-1.75 (m, 2H), 2.32-2.47 (m, 2H), 2.56-2.90 (m, 3H), 3.15-3.22 (m, 3H), 3.42-3.47 (m, 1H), 3.63 (m, 1H), 3.97 (m, 1H), 4.08, 4.10 and 4.13 (three d, 1H), 4.15, 4.24 and 4.38 (three d, 1H), 4.48, 4.54 and 4.56 (three t, 2H), 4.894.93 and 5.02 (three d, 1H), 5.36, 5.38 and 5.44 (three d, 1H), 6.61 (m, 4H), 6.76-6.79 (m, 2H), 7.02-7.06 (m, 2H), 7.18-7.31 (m, 5H), 9.28, 9.33,9.34, 9.39, 9.47 and 9.49 (six s, 2H). Mass spectrum: (M+H)+ = 520.
Anal. Calcd. for C29H33N3O6.H2O: C, 64.79; H, 6.56; N, 7.82;
Found: C, 64.83; H, 6.38; N, 7.72.
Example 23
A. (5 R,6R)-1-(benzyloxyacetvh-5-benzyl-6-(trimethylsilylethoxymethoxy)-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of 1J , but replacing the benzoyl chloride with benzyloxyacetyl chloride, provided the desired compound. Mass spectrum: (M+NH)+ = 500.
B. (5R,6R)-1-(hydroxyacetyn-5-benzyl-6-(trimethylsilylethoxy-methoxy)-3-oxo-1,2,4-triazacycloheptane.
To a suspension of 150 mg of 10% palladium on carbon in 10 ml of ethanol (95%) was added 143.8 mg of the product of Example 23A. The mixture was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 2 days. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 103.2 mg of the desired product. Mass spectrum: (M+NH4)+ = 427.
C. (5R,6R)-1-(trimethylsilylethoxymethoxyacetyl)-5- benzyl-6-(trimethylsilylethoxymethoxy)-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1F, but replacing the product of 1 E with the product of Example 23B, provided the desired compound. Mass spectrum: (M+NH)+ = 540. D. (5R,6R)-2,4-Bis-(4-hydroxybenzyh-1-hydroxy- acetyl-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 23C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. 1H NMR (DMSO-D6) (mixture of three rotamers) δ 2.58-2.79 (m, 3H), 3.10-3.25 (m, 2H), 3.39-3.48 (m, 1H), 3.65 (m, 1H), 3.87 (m, 1H), 4.08 (d, 1H), 4.33, 4.39 and 4.46 (three d, 2H), 4.80, 4.94 and 4.95 (three d, 1H), 5.43, 5.46 and 5.61 (three d, 1H), 6.64-6.76 (m, 6H), 7.03-7.33 (m, 7H), 7.73, 7.98 and 8.12 (three s, 1H), 9.30,9.33, 9.35, 9.43, 9.47 and 9.50 (six s, 2H). Mass
spectrum: (M+NH4)+ = 509.
Example 24
(5R,6R)-2,4-Bis-(3-nitrobenzyl)-1-(3-methyl- butyryl)-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 3-nitrobenzyl bromide, provided the desired compound. 1H NMR (DMSO-d6) (mixture of three rotamers) 0.65-0.94 (six d, 6H), 1.54-2.37 (m, 4H), 2.64-3.22 (m, 3H), 3.32-4.18 (m, 3H), 4.26-4.32 (m, 1H), 4.48-4.60 (m, 1H), 5.14, 5.17 and 5.18 (three d, 1H), 5.46, 5.50 and 5.51 (three d, 1H), 6.86-8.41 (m, 13H). Mass spectrum: (M+ H)+ =576.
Anal. Calcd. for C30H33N5O7.0.5H2O: C, 61.63; H, 5.86; N, 11.98; Found: C, 61.70; H, 5.65; N, 11.72.
Example 25
(5R,6R)-2,4-Bis-(3-aminobenzyn-1-(3-methyl- butyryn-5-benzyl-6-hydroxy-3-oxo-1,2,4- triazacycloheptane.
To a suspension of 150 mg of Raney-Ni (50% in water) in 15 ml of MeOH/THF (1:1) was added 150 mg of the product of Example 24. The reaction mixture was stirred vigorously under a hydrogen atmosphere (hydrogen filled balloon) for 2 h. Filtration,
concentration in vacuo and purification by silica gel column
chromatography using 5% MeOH in CH2CI2 provided 119.0 mg (89%) of desired product as a white foam. 1H NMR (DMSO-d6) (mixture of three rotamers) 0.84-0.97 (six d, 6H), 1.82-2.63, (m, 4H), 2.80-4.04 (m, 6H), 3.92, 4.06 and 4.13 (three d, 1H), 4.24, 4.39 and 4.52 (three d, 1H), 4.87-5.11 (m, 5H), 5.30, 5.32 and 5.38 (three d, 1H), 5.95-6.03 (m, 2H), 6.37-7.32 (m, 11H). Mass spectrum: (M+H)+ = 516.
Anal. Calcd. for C30H37N5O3.0.25H2O: C, 69.27; H, 7.27; N, 13.46; Found: C, 69.34; H, 7.21; N, 13.34.
Example 26
(5R,6R)-2,4-Bis-(4-nitrobenzyl)-1-(3-methylbutyryl)-5- benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 4-nitrobenzyl bromide, provided the desired compound. 1 H NMR (DMSO-d6) (mixture of two rotamers) 0.68-0.94 (four d, 6H), 1.57-2.38, (m, 4H), 2.63-3.20 (m, 3H), 3.31-4.16 (m, 3H), 4.25 and 4.31 (two d, 1H), 4.49 and 4.57 (two dd, 1H), 5.15 and 5.16 (two d, 1H), 5.44 and 5.49 (two d, 1H), 6.86-8.32 (m, 13H). Mass spectrum: (M+ H)+ =576.
Anal. Calcd. for C30H33N5O7.0.5H2O: C, 61.63; H, 5.86; N, 11.98; Found: C, 61.70; H, 5.65; N, 11.72.
Example 27
(5R,6R)-2,4-Bis-(4-aminobenzyl)-1-(3-methylbutyryl)-5 benzyl-6-hydroxy-3-oxo-1,2,4-triazacycloheptane.
Using the procedure of Example 25, but replacing the product of Example 24 with the product of Example 26, provided the desired compound. 1H NMR (DMSO-d6) (mixture of three rotamers) 0.85-0.99 (four d, 6H), 1.81-2.58, (m, 4H), 2.63-3.98 (m, 6H), 3.90, 4.04 and 4.12 (three d, 1 H), 4.18, 4.32 and 4.51 (three d, 1 H), 4.81 -5,09 (m, 5H), 5.28, 5.31 and 5.40 (three d, 1 H), 6.38-6.56 (m, 6H), 6.98-7.31 (m, 7H). Mass spectrum: (M+ H)+ =516.
Anal. Calcd. for C30H37N5O3.0.5H2O: C, 68.68; H, 7.30; N, 13.35; Found: C, 68.80; H, 7.15; N, 13.17.
Using the methods described above, the compounds shown in
Tables 1 -128 can be prepared. In the tables, Ph represents phenyl.
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Fluorogenic Assay for Screening Inhibitors of HIV Protease
The inhibitory potency of the compounds of the invention can be determined by the following method.
A compound of the invention is dissolved in DMSO and a small aliquot further diluted with DMSO to 100 times the final concentration desired for testing. The reaction is carried out in a 6 X 50 mm tube in a total volume of 300 microliters. The final concentrations of the components in the reaction buffer are: 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 μM fluorogenic substrate, 2% (v/v)
dimethylsulfoxide, pH 4.5. After addition of inhibitor, the reaction mixture is placed in the fluorometer cell holder and incubated at 30°C for several minutes. The reaction is initiated by the addition of a small aliquot of cold HIV protease. The fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time. The reaction rate is determined for the first six to eight minutes. The observed rate is directly proportional to the moles of substrate cleaved per unit time. The percent inhibition is 100 X (1 - (rate in presence of inhibitor)/(rate in absence of inhibitor)).
Fluorogenic substrate: Dabcyl-Ser-Gln-Asn-Tyr-Pro-lle-Val-Gln-EDANS wherein DABCYL - 4-(4-dimethylamino-phenyl)azobenzoic acid and EDANS = 5-((2-aminoethyl)amino)-naphthalene-1 -sulfonic acid.
Table I shows the inhibitory potencies of compounds of the invention against HIV-1 protease.
Figure imgf000146_0001
Antiviral Activity
The anti-HIV activity of the compounds of the invention can be determined in MT4 cells according to the procedure of Kempf, et. al.
(Antimicrob. Agents Chemother. 1991 , 35, 2209). The IC50 is the
concentration of compound that gives 50% inhibition of the cytopathic effect of HIV. The LC50 is the concentration of compound at which 50% of the cells remain viable.
Table II shows the inhibitory potencies of compounds of the invention against HIV-138 in MT4 cells.
Figure imgf000147_0001
Figure imgf000148_0001
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen- containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
The compounds of the present invention can also be used in the form of esters. Examples of such esters include a hydroxyl-substituted compound of formula A or B which has been acylated with a naturally occurring α-amino acid residue which is optionally N-protected, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R*C(O)- or R*C(S)- wherein R* is hydrogen, loweralkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C(Rb)(Rd)-C(O)- or Ra- C(Rb)(Rd)-C(S)- wherein Rb and Rd are independently selected from hydrogen and loweralkyl and Ra is -N(Re)(Rf), -ORe or -SRe wherein Re and Rf are independently selected from hydrogen, loweralkyl and haloalkyi, or an amino- acyl residue of the formula R180NH(CH2)2NHCH2C(O)- or
R180NH(CH2)2OCH2C(O)- wherein R1 80 is hydrogen, loweralkyl, arylalkyl. cycloalkylalkyl, alkanoyl, benzoyl or a naturally occurring α-amino acyl group. The amino acid esters of particular interest are those derived from the naturally occurring α-amino acids, however, other amino acid residues can also be used, including those wherein the amino acyl group is -C(O)CH2NR200R201 wherein R200 and R201 are independently selected from hydrogen and loweralkyl or the group -NR200 R201 forms a nitrogen containing heterocyclic ring. These esters serve as pro-drugs of the compounds of the present invention and also serve to increase the solubility of these substances in the gastrointestinal tract. These esters also serve to increase solubility for intravenous administration of the compounds. Other prodrugs include a hydroxyl-substituted compound of formula A or B wherein the hydroxyl group is functionalized with a substituent of the formula -CH(Rg)OC(O)R181 or -CH(Rg)OC(S)R181 wherein R181 is loweralkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and Rg is hydrogen, loweralkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.
The prodrugs of this invention are metabolized in vivo to provide the hydroxyl-substituted compound of formula A or B. The preparation of the prodrug esters is carried out by reacting a hydroxyl-substituted compound of formula A or B with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to provide the desired pro-drug ester. Prodrugs of the invention can also be prepared by alkylation of the hydroxyl group with (haloalkyl)esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
The compounds of the invention are useful for inhibiting retroviral protease, in particular HIV protease, in vitro or in vivo (especially in mammals and in particular in humans). The compounds of the present invention are also useful for the inhibition of retroviruses in vivo, especially human
immunodeficiency virus (HIV). The compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, in a human or other mammal.
Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from about 0.001 to about 1000 mg/kg body weight daily and more usually from about 0.1 to about 50 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as
magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents, other antiinfective agents or vaccines. Other antiviral agents to be administered in combination with a compound of the present invention include AL-721 , beta interferon,
polymannoacetate, reverse transcriptase inhibitors ( for example, zalcitabine (ddC), didanosine (ddl), BCH-189, AzdU, carbovir, DDA, D4C, stavudine (d4T), DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia-dideoxycytidine, PMEA, zidovudine (AZT) and the like), non-nucleoside reverse transcriptase inhibitors (for example, R82193, L-697,661 , BI-RG-587 (nevirapine), retroviral protease inhibitors (for example, HIV protease inhibitors such as Ro 31 -8959, SC-52151 , KNI-227, KNI-272 and the like), HEPT compounds, L,697,639, R82150, U- 87201 E and the like), TAT inhibitors (for example, RO-24-7429 and the like), trisodium phosphonoformate, HPA-23, eflonithine, Peptide T, Reticulose
(nucleophosphoprotein), ansamycin LM 427, trimetrexate, UA001 , ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cylobut-G, cyclobut-A, ara-M, BW882C87, foscamet, BW256U87, BW348U87, L-693,989, BV ara-U, CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109, TI-23, trifluridine, vidarabine, famciclovir, penciclovir, acyclovir, ganciclovir, castanospermine, rCD4/CD4-lgG, CD4-PE40, butyl-DNJ, hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate. Immunomodulators that can be administered in combination with a compound of the present invention include bropirimine, Ampligen, anti-human alpha interferon antibody, colony stimulting factor, CL246,738, lmreg-1 , lmreg-2, diethydithiocarbamate, interleukin-2, alpha- interferon, inosine pranobex, methionine enkephalin, muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis facator, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha interferon immunoglobulin, IGF-1 , anti-Leu-3A, autovaccination, biostimulation, extracorporeal photophoresis, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine, IVIG, HIVIG, passive immunotherapy and polio vaccine
hyperimmunization. Other antiinfective agents that can be administered in combination with a compound of the present invention include pentamidine isethionate. Any of a variety of HIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with a
compound of the present invention.
Other agents that can be used in combination with the compounds of this invention are ansamycin LM 427, apurinic acid, ABPP, AI-721 , carrisyn, AS-101 , avarol, azimexon, colchicine, compound Q, CS-85, N-acetyl cysteine, (2- oxothiazolidine-4-carboxylate), D-penicillamine, diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1 , monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T, pine cone extract, polymannoacetate, reticulose, retrogen, ribavirin, ribozymes, RS-47, Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin, thymosin fraction 5, thymosin alpha one, thymostimulin, UA001 , uridine, vitamin B12 and
wobemugos.
Other agents that can be used in combination with the compounds of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin and the like.
Other agents that can be used in combination with the compounds of this invention are antibactehals such as amikacin sulfate, azithromycin,
ciprofloxacin, tosufloxacin, clarithromycin, clofazimine, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65 and the like.
Other agents that can be used in combination with the compounds of this invention are anti-neoplasties such as alpha interferon, COMP
(cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP(prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, etoposide/mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine,
angioinhibins, pentosan polysulfate, platelet factor 4 and SP-PG and the like.
Other agents that can be used in combination with the compounds of this invention are drugs for treating neurological disease such as peptide T, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparin and cytosine arabinoside and the like.
Other agents that can be used in combination with the compounds of this invention are anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflomithine, 566C80, fansidar, furazolidone, L, 671 , 329, letrazuril, metronidazole, paromycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.
Among the preferred agents for treatment of HIV or AIDS in combination with the compounds of this invention are reverse transcriptase inhibitors.
It will be understood that agents which can be combined with the compounds of the present invention for the treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but include in principle any agents useful for the treatment or prophylaxis of AIDS or an HIV infection.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

CLAIMSWhat is claimed is:
1. A compound of the formula:
Figure imgf000155_0001
Figure imgf000155_0002
Figure imgf000156_0001
R2 is R2a-C(O)- or R2a-S(O)2- wherein R2a is selected from:
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
X is
(i) -C(=Y)- wherein Y is O, S or N(R5) wherein R5 is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro;
(ii) -S(O)- or
(iii) -S(O)2-;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
2. The compound of Claim 1 wherein R1 is loweralkyl or arylalkyi; R2 is R2a-C(O)- wherein R2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R3 and R4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, arylalkyl or (heterocyclic)alkyl; and X is -C(=O)-, -C(=N-OH)-, -C(=N-CN)- or -S(O)2-.
3. The compound of Claim 1 wherein R1 is loweralkyl, benzyl, alkoxy- substituted benzyl or halo-substituted benzyl; R2 is R2a-C(O)- wherein R2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyl; R3 and R4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, benzyl, hydroxy-substituted benzyl, hydroxyalkyl-substituted benzyl, alkoxy- substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substitutents are hydroxy and alkoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-, -C(=N- OH)-, -C(=N-CN)- or -S(O)2-.
4. The compound of Claim 1 wherein R1 is isobutyl, benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3-(CH2)2-, (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl, HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl- substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)- or -S(O)2-.
5. The compound of Claim 1 wherein R1 is isobutyl, benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3-(CH2)2-, (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl, HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl- substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-.
6. The compound of Claim 1 wherein R1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3- (CH2)2-, (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl,
HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-.
7. The compound of Claim 1 wherein R1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is
(CH3)2CHCH2-; R3 and R4 are independently selected from 4-hydroxybenzyl, 4- aminobenzyl and 3-aminobenzyl; and X is -C(=O)-.
8. The compound according to Claim 1 of the formula:
Figure imgf000161_0001
wherein R 1 , R2, R3, R4 and X are as defined therein.
9. The compound of Claim 8 wherein R1 is loweralkyl or arylalkyl; R2 is R2a-C(O)- wherein R2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyl; R3 and R4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, arylalkyl or (heterocyclic)alkyl; and X is -C(=O)-, -C(=N-OH)-, -C(=N-CN)- or -S(O)2-.
10. The compound of Claim 8 wherein R1 is loweralkyl, benzyl, alkoxy- substituted benzyl or halo-substituted benzyl; R2 is R2a-C(O)- wherein R2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R3 and R4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, benzyl, hydroxy-substituted benzyl, hydroxyalkyl-substituted benzyl, alkoxy- substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substitutents are hydroxy and alkoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-, -C(=N- OH)-, -C(=N-CN)- or -S(O)2-.
11. The compound of Claim 8 wherein R1 is isobutyl, benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3-(CH2)2-, (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl, HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl- substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)- or -S(O)2-.
12. The compound of Claim 8 wherein R1 is isobutyl, benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3-(CH2)2-, (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl, HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl- substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-.
13. The compound of Claim 8 wherein R1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is CH3-, CH3- (CH2)2-, (CH3)2CHCH2-, CH3(CH2)3-, (CH3(CH2)2)2CH-, cyclopentyl,
HOCH2(CH2)3-, HOCH2(CH2)2- or HOCH2-; R3 and R4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=O)-.
14. The compound of Claim 8 wherein R1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2 is R2a-C(O)- wherein R2a is
(CH3)2CHCH2-; R3 and R4 are independently selected from 4-hydroxybenzyl, 4- aminobenzyl and 3-aminobenzyl; and X is -C(=O)-.
15. A compound selected from the group consisting of:
(5R,6R)-2,4-Bis-(4-hydroxybenzyl)-1-(3-methylbutyryl)-5-benzyl- 6-hydroxy-3-oxo-1,2,4-triazacyclo heptane;
(5R,6R)-2,4-Bis-(3-aminobenzyl)-1-(3-methylbutyryl)-5-benzyl-6- hydroxy-3-oxo-1,2,4-triazacycloheptane; and
(5R,6R)-2,4-Bis-(4-aminobenzyl)-1-(3-methylbutyryl)-5-benzyl-6- hydroxy-3-oxo-1,2,4-triazacycloheptane;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
16. A method for inhibiting HIV protease comprising administering to a human in need thereof a therapeutically effective amount of a compound of Claim 1.
17. A method for inhibiting HIV protease comprising administering to a human in need thereof a therapeutically effective amount of a compound of Claim 8.
18. A method for inhibiting HIV protease comprising administering to a human in need thereof a therapeutically effective amount of a compound of Claim 15.
19. A method for inhibiting HIV comprising administering to a human in need thereof a therapeutically effective amount of a compound of Claim 1.
20. A method for inhibiting HIV comprising administering to a human in need thereof a therapeutically effective amount of a compound of Claim 8.
21. A method for inhibiting HIV comprising administering to a human in need thereof a therapeutically effective amount of a compound of Claim 15.
22. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
23. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 8.
24. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 15.
25. A compound of the formula:
Figure imgf000164_0001
Figure imgf000164_0002
Figure imgf000165_0001
Figure imgf000166_0001
R8 is hydrogen or an O-protecting group; and
R9 and R 10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.
26. The compound according to Claim 25 of the formula:
Figure imgf000167_0001
wherein R1, R2, R8, R9 and R10 are as defined therein.
27. The compound of Claim 24 wherein R 1 is loweralkyl or arylalkyl and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl,
di-(methoxyphenyl)methyl or triphenylmethyl.
28. The compound of Claim 24 wherein R1 is loweralkyl, benzyl, alkoxy- substituted benzyl or halo-substituted benzyl; R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
29. The compound of Claim 24 wherein R1 is isobutyl, benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl; R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
30. The compound of Claim 24 wherein R1 is isobutyl, benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
31. The compound of Claim 24 wherein R1 is benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
32. The compound of the formula:
Figure imgf000168_0001
Figure imgf000169_0001
R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-
(methoxyphenyl)methyl or triphenylmethyl;
R8 is hydrogen or an O-protecting group; and
X is (i) -C(=Y)- wherein Y is O, S or N(R5) wherein R5 is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro;
(ii) -S(O)- or
(iii) -S(O)2-;
or a salt thereof.
33. The compound according to Claim 32 of the formula:
Figure imgf000170_0001
wherein R1 , R2a, R8 and X are as defined therein.
34. The compound of Claim 32 wherein R 1 is loweralkyl or arylalkyl; R2 is benzyl and R8 is an O-protecting group.
35. The compound of Claim 32 wherein R1 is loweralkyl, benzyl, alkoxy- substituted benzyl or halo-substituted benzyl and X is -C(=O)-.
36. The compound of Claim 32 wherein R1 is isobutyl, benzyl, methoxy- substituted benzyl or fluoro-substituted benzyl and X is -C(=O)-.
37. A process for the preparation of a compound of Claim 1 comprising reacting a compound of the formula:
Figure imgf000171_0002
wherein R1 , R2, R8 and X are as defined therein with R4-Z" wherein Z" is a leaving group and R4 is as defined therein, followed by reaction of the resulting product with R3-Z' wherein Z' is a leaving group and R3 is as defined therein.
38. A process for the preparation of a compound of Claim 8 comprising reacting a compound of the formula:
Figure imgf000171_0001
wherein R1 , R2, R8 and X are as defined there with R4-Z" wherein Z" is a leaving group and R4 is as defined therein, followed by reaction of the resulting product with R3-Z' wherein Z' is a leaving group and R3 is as defined therein.
PCT/US1995/009472 1994-08-09 1995-07-26 Retroviral protease inhibiting 1,2,4-triazacycloheptanes WO1996005180A1 (en)

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